Guideline:
Drotrecogin alfa (activated) for severe sepsis
Bibliographic Source(s)
- National Institute for Clinical Excellence (NICE). Drotrecogin alfa (activated) for severe sepsis. London (UK): National Institute for Clinical Excellence (NICE); 2004 Sep. 31 p. (Technology appraisal; no. 84).
Guideline Status
This is the current release of the guideline.
Guideline Category
Assessment of Therapeutic Effectiveness
Treatment
Intended Users
Advanced Practice Nurses
Physician Assistants
Physicians
Guideline Objective(s)
To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis
Target Population
Adults with severe sepsis
Interventions and Practices Considered
Drotrecogin alfa (activated) (recombinant human activated protein C [rhAPC]) (Xigris™)
Major Outcomes Considered
- Clinical effectiveness
The primary outcome measure was all-cause mortality at the end of study follow-up. The side effect profile of drotrecogin alfa (activated) was also covered. Additional secondary outcome measures that were considered include:
- Death from septic shock
- Length of hospital and/or ICU stay
- Functional status (quality of life)
- Acute Physiology Age and Chronic Health Evaluation (APACHE) II scores
- Number of organ failures
- Organ dysfunction
- Duration of assisted ventilation
- Nosocomial infection
- Cost-effectiveness
Methods Used to Collect/Select Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data
Description of Methods used to Collect/Select the Evidence
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the Southampton Health Technology Assessments Centre (SHTAC) (see the "Companion Documents" field).
Search Strategy
Extensive electronic searches were conducted by an experienced information scientist to identify both published and unpublished literature including existing systematic reviews and primary studies evaluating the effectiveness of drotrecogin alfa (activated) relevant quality of life literature and economic evaluations.
The databases searched and search strategy used are documented in Appendix 3 of the assessment report.
Further useful citations were retrieved through scanning the reference lists of all retrieved studies and contact with experts. Sponsor and other submissions were also checked for:
- Any additional studies or additional unpublished data relating to previously identified studies meeting the inclusion criteria
- Relevant cost data
- Data on current use of drotrecogin alfa (activated) for severe sepsis in England and Wales
The titles and abstracts retrieved by the electronic searches were screened independently by two reviewers; the full papers for each study selected were obtained and assessed for inclusion again by two reviewers. Any disagreements were resolved through discussion with referral to a third reviewer where necessary. Reasons for exclusion of full papers were formally documented. Any "commercial in confidence" data taken from sponsor's submission has been clearly marked (underlined) in the report submitted to the Health Technology Assessment (HTA programme and to the National Institute for Health and Clinical Excellence (NICE). A separate version with any such data removed has also been submitted.
Inclusion Criteria and Exclusion Criteria
Participants
Hospitalised adult patients with severe sepsis or septic shock acquired either in the community or in the hospital. Severe sepsis is defined according to internationally accepted guidelines as set out by American College of Chest Physicians/Society of Critical Care Medicine in 1992. Studies conducted in children (aged <18 years) were excluded.
Interventions
Drotrecogin alfa (activated) (i.e. recombinant human activated protein C) plus conventional care compared to conventional care alone.
Study Design
In order to establish the effectiveness of the intervention only randomised controlled trials (RCTs) were included. To establish the safety of the drug all studies conducted in relevant participants were included. The generalisability of the available trial results to the United Kingdom (UK) context were estimated by comparing the participants and care used in the available RCT(s) to that in the UK.
Outcome Measures
The expert panel for the review were consulted to determine the most appropriate outcome measures for the review. See the "Major Outcomes Considered" field in this summary.
Quality Assessment and Data Extraction Strategy
Quality assessment of RCTs was conducted according to the guidelines of the Cochrane Infectious Diseases Group with the addition of some topic-specific items relevant to trials conducted in people with sepsis (see Appendix 4 of the Assessment Report).
Data extraction and quality assessment were conducted independently by two reviewers using pre-designed forms. Any disagreements were resolved through discussion with referral to a third reviewer if necessary.
Number of Source Documents
Quantity of Research Available
A total of 1016 titles and abstracts were retrieved from the literature searches and from screening the reference lists. The Assessment Centre obtained 108 full papers and from these seven full papers and three abstracts were selected for inclusion in the review. A flowchart of the results of the search and inclusion/exclusion decisions is provided at Figure 1 and a list of excluded studies is provided in Appendix 5 of the assessment report.
Two randomised controlled trials (RCTs) assessing the effectiveness of drotrecogin alfa (activated) were identified results for one having been published in five subsequent papers. The U.S. Food and Drug Administration (FDA) have also published a clinical review of recombinant human activated protein C (rhAPC) to support their licensing decision. This includes data not available in the other trial publications and also reports some exploratory analyses of the trial data. A cumulative safety review provides data from the two RCTs plus three otherwise unpublished prospective open-label studies and data from the commercial use of the drug up to April 2002.
Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus
Rating Scheme for the Strength of the Evidence
Not applicable
Methods Used to Analyze the Evidence
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence
Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Clinical Excellence (NICE) commissioned an independent academic centre to perform a systematic literature review on the technology considered in this appraisal and prepare an assessment report. The assessment report for this technology appraisal was prepared by the Southampton Health Technology Assessments Centre (SHTAC) (see the "Companion Documents" field).
Methods of Analysis/Synthesis
For the primary endpoint trial data are presented as relative risks and 95% confidence intervals (CI). Continuous data such as length of hospital stay are presented as mean and standard deviation. Data for the following subgroups are thought to be of particular relevance: severity of disease at baseline e.g. Acute Physiology Age and Chronic Health Evaluation (APACHE) II score; number of organ failures; source and site of infection e.g. hospital vs. community acquired.
For the assessment of side effects incidence all available data on the clinical use of drotrecogin alfa (activated) in patients with severe sepsis was included.
Prospective observational data from Intensive Care National Audit and Research Centre (ICNARC) was obtained and used to examine the generalisability of the trial results to the United Kingdom setting.
Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations
Considerations
Technology appraisal recommendations are based on a review of clinical and economic evidence.
Technology Appraisal Process
The National Institute for Health and Clinical Excellence (NICE) invites 'consultee' and 'commentator' organisations to take part in the appraisal process. Consultee organisations include national groups representing patients and carers the bodies representing health professionals and the manufacturers of the technology under review. Consultees are invited to submit evidence during the appraisal and to comment on the appraisal documents.
Commentator organisations include manufacturers of the products with which the technology is being compared the National Health Service (NHS) Quality Improvement Scotland and research groups working in the area. They can comment on the evidence and other documents but are not asked to submit evidence themselves.
NICE then commissions an independent academic centre to review published evidence on the technology and prepare an 'assessment report'. Consultees and commentators are invited to comment on the report. The assessment report and the comments on it are then drawn together in a document called the evaluation report.
An independent Appraisal Committee then considers the evaluation report. It holds a meeting where it hears direct spoken evidence from nominated clinical experts patients and carers. The Committee uses all the evidence to make its first recommendations in a document called the 'appraisal consultation document' (ACD). NICE sends all the consultees and commentators a copy of this document and posts it on the NICE website. Further comments are invited from everyone taking part.
When the Committee meets again it considers any comments submitted on the ACD; then it prepares its final recommendations in a document called the 'final appraisal determination' (FAD). This is submitted to NICE for approval.
Consultees have a chance to appeal against the final recommendations in the FAD. If there are no appeals the final recommendations become the basis of the guidance that NICE issues.
Who is on the Appraisal Committee?
NICE technology appraisal recommendations are prepared by an independent committee. This includes health professionals working in the NHS and people who are familiar with the issues affecting patients and carers. Although the Appraisal Committee seeks the views of organisations representing health professionals patients carers manufacturers and government its advice is independent of any vested interests.
Rating Scheme for the Strength of the Recommendations
Not applicable
Cost Analysis
Literature Search and Methods
The literature search undertaken by the Assessment Group identified three published cost-effectiveness analyses that were performed from a North American perspective. The Assessment Group also identified six published abstracts and two unpublished abstracts. The manufacturer provided two economic evaluations (one based on PROWESS day-28 data and one on the follow-up information available) and a model as part of its submission. In addition the Assessment Group developed a model to assess the cost effectiveness of drotrecogin alfa (activated) plus conventional care versus conventional care alone in a UK cohort of adult patients with severe sepsis.
Summary
The United Kingdom analyses indicate a cost per quality-adjusted life year (QALY) of less than 11000 pounds sterling for patients with severe sepsis and multiple organ failure treated with drotrecogin alfa (activated). If all patients are considered the cost per QALY profile becomes less favourable. Other available studies are broadly consistent with these findings although North American estimates of cost per QALY are higher.
See Section 4.2 of the original guideline document for a detailed discussion and more information.
Method of Guideline Validation
External Peer Review
Description of Method of Guideline Validation
Consultee organizations from the following groups were invited to comment on the draft scope Assessment Report and the Appraisal Consultation Document (ACD) and were provided with the opportunity to appeal against the Final Appraisal Determination.
- Manufacturer/sponsors
- Professional/specialist and patient/carer groups
- Commentator organisations (without the right of appeal)
In addition individuals selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups were also invited to comment on the ACD.
Major Recommendations
Note from the National Guideline Clearinghouse (NGC) and the National Institute for Health and Clinical Excellence (NICE): Since the NICE guidance on drotrecogin alpha (activated) was issued the European Medicines Evaluation Agency (EMEA) has recommended changes to the way that drotrecogin alpha (activated) should be used. Please see the "Regulatory Alert" field for more information. NICE advises that clinicians wishing to prescribe drotrecogin alpha (activated) should take the EMEA advice into account alongside the guidance from NICE when deciding whether or not to prescribe drotrecogin alpha (activated).
- Drotrecogin alfa (activated) is recommended for use in adult patients who have severe sepsis that has resulted in multiple organ failure (that is two or more major organs have failed) and who are being provided with optimum intensive care support.
- The use of drotrecogin alfa (activated) should only be initiated and supervised by a specialist consultant with intensive care skills and experience in the care of patients with sepsis.
Clinical Algorithm(s)
None provided
Type of Evidence supporting the Recommendations
The type of evidence supporting the recommendations is not specifically stated.
Potential Benefits
Appropriate use of drotrecogin alfa (activated) for the treatment of severe sepsis
Potential Harms
Drotrecogin alfa (activated) may increase bleeding.
For full details of side effects and contraindications see the Summaries of Product Characteristics available at http://emc.medicines.org.uk/.
Contraindications
Drotrecogin alfa (activated) may increase bleeding and consequently it is contraindicated in certain patients such as those with active internal bleeding.
For full details of side effects and contraindications see the Summaries of Product Characteristics available at http://emc.medicines.org.uk/.
Qualifying Statements
This guidance represents the view of the Institute which was arrived at after careful consideration of the available evidence. Health professionals are expected to take it fully into account when exercising their clinical judgement. This guidance does not however override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patient in consultation with the patient and/or guardian or carer.
Description of Implementation Strategy
Implementation and Audit
- All clinicians who care for adults with severe sepsis and multiple organ failure should review their current practice and policies to take account of the guidance set out in Section 1 of the original guideline document (and the "Major Recommendations" field).
- Intensive care units in National Health Service hospitals should define the clinical circumstances in which drotrecogin alfa (activated) is to be used and the training and experience of consultants who are authorised to initiate and supervise the treatment.
- To measure compliance locally with the guidance the following criteria could be used. Further details on suggestions for audit are presented in Appendix C of the original guideline document.
- Drotrecogin alfa (activated) is used for an adult with severe sepsis that has resulted in multiple organ failure and who is being provided with optimum intensive care support.
- The use of drotrecogin alfa (activated) is initiated and supervised only by a specialist consultant with intensive care skills and experience in the care of patients with sepsis.
Implementation Tools
Audit Criteria/Indicators
Foreign Language Translations
Patient Resources
Quick Reference Guides/Physician Guides
For information about availability see the "Availability of Companion Documents" and "Patient Resources" fields below.
IOM Care Need
Getting Better
IOM Domain
Effectiveness
Patient-centeredness
Bibliographic Source(s)
- National Institute for Clinical Excellence (NICE). Drotrecogin alfa (activated) for severe sepsis. London (UK): National Institute for Clinical Excellence (NICE); 2004 Sep. 31 p. (Technology appraisal; no. 84).
Adaptation
Not applicable: The guideline was not adapted from another source.
Source(s) of Funding
National Institute for Health and Clinical Excellence (NICE)
Guideline Committee
Appraisal Committee
Composition of Group that Authored the Guideline
Dr Jane Adam Radiologist St George's Hospital London; Professor Ron Akehurst Dean of School of Health and Related Research University of Sheffield; Dr Sunil Angris General Practitioner Waterhouses Medical Practice Staffordshire; Professor David Barnett (Chair) Professor of Clinical Pharmacology University of Leicester; Professor Stirling Bryan Professor of Health Economics Health Economics Facility Health Services Management Centre University of Birmingham; Professor John Cairns Professor of Health Economics Health Economics Research Unit University of Aberdeen; Professor David Chadwick Professor of Neurology Department of Neurological Science Walton Centre for Neurology & Neurosurgery Liverpool; Ms Ailsa Claire Chief Executive Barnsley Primary Care Trust South Yorkshire; Dr Lorna Duggan Consultant Forensic Psychiatrist in Developmental Disabilities St Andrew's Hospital Northampton; Mrs Fiona Duncan Clinical Nurse Specialist Anaesthetic Department Blackpool Victoria Hospital Blackpool; Dr Paul Ewings Statistician Taunton & Somerset NHS Trust Taunton; Mr Sanjay Gupta Stroke Services Manager Basildon & Thurrock University Hospitals NHS Trust; Professor Philip Home (Vice-Chair) Professor of Diabetes Medicine Department of Medicine University of Newcastle upon Tyne; Dr Peter Jackson Clinical Pharmacologist Molecular & Clinical Pharmacology University of Sheffield; Dr Mike Laker Medical Director Newcastle Hospitals NHS Trust Royal Victoria Infirmary Newcastle upon Tyne; Professor Richard Lilford Professor of Clinical Epidemiology Department of Public Health and Epidemiology University of Birmingham; Dr Simon Mitchell Consultant Neonatal Paediatrician St Mary's Hospital Manchester; Dr Virginia Pearson Chief Executive South Petherton Hospital South Somerset PCT; Dr Christa Roberts Industry Representative UK Manager Vascular Intervention Guidant Ltd Basingstoke Hampshire; Dr Stephen Saltissi Consultant Cardiologist Royal Liverpool University Hospital; Dr Lindsay Smith General Practitioner Westlake Surgery Somerset; Mr Mike Spencer General Manager Clinical Support Services Cardiff and Vale NHS Trust; Dr Rod Taylor Senior Lecturer Department of Public Health & Epidemiology University of Birmingham; Professor Norman Waugh Department of Public Health University of Aberdeen; Mrs Miranda Wheatley-Price Lay Representative Director of Service Development Colon Cancer Concern London
Financial Disclosures/Conflicts of Interest
Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest the member is excluded from participating further in that appraisal.
Guideline Status
This is the current release of the guideline.
Guideline Availability
Electronic copies: Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site.
Print copies: Available from the National Health Service (NHS) Response Line 0870 1555 455. 11 Strand London WC2N 5HR.
Availability of Companion Documents
The following are available:
- Drotrecogin alfa (activated) for severe sepsis. Quick reference guide. London (UK): National Institute for Health and Clinical Excellence (NICE); 2004 Sep. 2 p. (Technology appraisal 84). Electronic copies: Available in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site.
- The clinical and cost-effectiveness of drotrecogin alfa (activated) (Xigris™) for the treatment of severe sepsis in adults: a systematic review and economic evaluation (excluding commercial in confidence data). Assessment report. Southampton (UK): Southampton Health Technology Assessments Centre (SHTAC); 2003 Dec. 157 p. (Technology appraisal 84). Electronic copies: Available in PDF from the National Institute for Health and Clinical Excellence (NICE) Web site.
Print copies: Available from the National Health Service (NHS) Response Line 0870 1555 455. 11 Strand London WC2N 5HR.
Additionally Audit Criteria can be found in Appendix C of the original guideline document.
Patient Resources
The following is available:
- Drotrecogin alfa (activated) for severe sepsis: understanding NICE guidance - information for the families and carers of people with severe sepsis and the public. London: National Institute for Health and Clinical Excellence. 2004 Sep. 10 p. Available in English and Welsh in Portable Document Format (PDF) from the National Institute for Health and Clinical Excellence (NICE) Web site.
Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.
NGC STATUS
This NGC summary was completed by ECRI on November 10 2005. This summary was updated by ECRI on November 14 2006 following the U.S. Food and Drug Administration (FDA) advisory on Xigris.
The National Institute for Health and Clinical Excellence (NICE) has granted the National Guideline Clearinghouse (NGC) permission to include summaries of their Technology Appraisal guidance with the intention of disseminating and facilitating the implementation of that guidance. NICE has not verified this content to confirm that it accurately reflects the original NICE guidance and therefore no guarantees are given by NICE in this regard. All NICE technology appraisal guidance is prepared in relation to the National Health Service in England and Wales. NICE has not been involved in the development or adaptation of NICE guidance for use in any other country. The full versions of all NICE guidance can be found at www.nice.org.uk.
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Tools
No Quick Reference tools have been developed.