An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis
Background: Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
NIHR Journals Library
2012-02-01
|
| Series: | Health Technology Assessment |
| Subjects: | |
| Online Access: | https://doi.org/10.3310/hta16070 |
| _version_ | 1817992708535353344 |
|---|---|
| author | MO Soares NJ Welton DA Harrison P Peura MS Hari SE Harvey JJ Madan AE Ades SJ Palmer KM Rowan |
| author_facet | MO Soares NJ Welton DA Harrison P Peura MS Hari SE Harvey JJ Madan AE Ades SJ Palmer KM Rowan |
| author_sort | MO Soares |
| collection | DOAJ |
| description | Background: Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. Objectives: To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. Data sources: Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. Review methods: Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. Results: Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control – as an indicator of proper blinding to treatment as a proxy for study quality – associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. Limitations: As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. Conclusions: Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct. Funding: The National Institute for Health Research Health Technology Assessment programme. |
| first_indexed | 2024-04-14T01:29:51Z |
| format | Article |
| id | doaj.art-54a069635528465ab3ecfb692b7e40dc |
| institution | Directory Open Access Journal |
| issn | 1366-5278 2046-4924 |
| language | English |
| last_indexed | 2024-04-14T01:29:51Z |
| publishDate | 2012-02-01 |
| publisher | NIHR Journals Library |
| record_format | Article |
| series | Health Technology Assessment |
| spelling | doaj.art-54a069635528465ab3ecfb692b7e40dc2022-12-22T02:20:13ZengNIHR Journals LibraryHealth Technology Assessment1366-52782046-49242012-02-0116710.3310/hta1607008/70/01An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysisMO Soares0NJ Welton1DA Harrison2P Peura3MS Hari4SE Harvey5JJ Madan6AE Ades7SJ Palmer8KM Rowan9Centre for Health Economics, University of York, York, UKSchool of Social and Community Medicine, University of Bristol, Bristol, UKIntensive Care National Audit & Research Centre, London, UKCentre for Health Economics, University of York, York, UKGuy’s and St Thomas’ Hospital NHS Foundation Trust, London, UKIntensive Care National Audit & Research Centre, London, UKSchool of Social and Community Medicine, University of Bristol, Bristol, UKSchool of Social and Community Medicine, University of Bristol, Bristol, UKCentre for Health Economics, University of York, York, UKIntensive Care National Audit & Research Centre, London, UKBackground: Sepsis is a syndrome characterised by a systemic inflammatory response to infection that leads to rapid acute organ failure and potentially rapid decline to death. Intravenous immunoglobulin (IVIG), a blood product derived from human donor blood, has been proposed as an adjuvant therapy for sepsis. Objectives: To describe current practice in the management of adult patients severely ill with sepsis (severe sepsis or septic shock) in the UK; to assess the clinical effectiveness of IVIG for severe sepsis and septic shock and to obtain the appropriate inputs for the relative efficacy parameters, and the key uncertainties associated with these parameters, required to populate the decision model; to develop a decision-analytic model structure and identify key parameter inputs consistent with the decision problem and relevant to an NHS setting; and to populate the decision model and determine the cost-effectiveness of IVIG and to estimate the value of additional primary research. Data sources: Existing literature on IVIG and severe sepsis. Existing case-mix and outcome data on critical care admissions. Survey data on management of admissions with severe sepsis. Databases searched for clinical effectiveness were Cochrane Infectious Diseases Group Specialized Trials Register, the Cochrane Trials Register, MEDLINE and EMBASE. Dates searched were 1 January 2002 to 2 October 2009 to update previous Cochrane review. Databases searched for cost-effectiveness were NHS Economic Evaluation Database (NHS EED) to 2 October 2009, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations and EMBASE to 20 October 2009. Review methods: Systematic literature searching with data extraction, descriptive analysis and clinical effectiveness and cost-effectiveness modelling of IVIG in severe sepsis. Additional primary data analysis. Expected value of information (EVI) analysis. Results: Our meta-analysis, the first to simultaneously allow for type of IVIG (IVIG or immunoglobulin M-enriched polyclonal IVIG), choice of control (no treatment or albumin), study quality/publication bias and other potential covariates, indicated that the treatment effect of IVIG on mortality for patients with severe sepsis is borderline significant with a large degree of heterogeneity in treatment effect between individual studies. Modelling indicated that there were issues with bias associated with trial methodology, publication and small-study effects with the current evidence. The large degree of heterogeneity in treatment effects between studies, however, could be explained (best-fitting model) by a measure of study quality (i.e. use of albumin as control – as an indicator of proper blinding to treatment as a proxy for study quality – associated with decreased effect) and duration of IVIG therapy (longer duration associated with increased effect). In-depth discussion within the Expert Group on duration of IVIG therapy, with daily dose and total dose also clearly inter-related, indicated no clear clinical rationale for this association and exposed a lack of evidence on the understanding of the mechanism of action of IVIG in severe sepsis. Although the EVI analyses suggested substantial expected net benefit from a large, multicentre randomised controlled trial (RCT) evaluating the clinical effectiveness of IVIG, the remaining uncertainties around the design of such a study mean that we are unable to recommend it at this time. Limitations: As has been identified in previous meta-analyses, there are issues with the methodological quality of the available evidence. Conclusions: Although the results highlight the value for money obtained in conducting further primary research in this area, the biggest limitation for such research regards the uncertainties over the mechanism of action of IVIG and the heterogeneous nature of severe sepsis. Resolving these would allow for better definition of the plausibility of the effectiveness scenarios presented and, consequently, a better understanding of the cost-effectiveness of this treatment. This information would also inform the design of future, primary evaluative research. Our recommendations for future research focus on filling the knowledge gaps to inform a future multicentre RCT prior to recommending its immediate design and conduct. Funding: The National Institute for Health Research Health Technology Assessment programme.https://doi.org/10.3310/hta16070systematic reviewmeta-analysisclinical effectivenesscost-effectivenessintravenous immunoglobulinsepsis |
| spellingShingle | MO Soares NJ Welton DA Harrison P Peura MS Hari SE Harvey JJ Madan AE Ades SJ Palmer KM Rowan An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis Health Technology Assessment systematic review meta-analysis clinical effectiveness cost-effectiveness intravenous immunoglobulin sepsis |
| title | An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis |
| title_full | An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis |
| title_fullStr | An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis |
| title_full_unstemmed | An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis |
| title_short | An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis |
| title_sort | evaluation of the feasibility cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis severe sepsis and septic shock incorporating a systematic review meta analysis and value of information analysis |
| topic | systematic review meta-analysis clinical effectiveness cost-effectiveness intravenous immunoglobulin sepsis |
| url | https://doi.org/10.3310/hta16070 |
| work_keys_str_mv | AT mosoares anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT njwelton anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT daharrison anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT ppeura anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT mshari anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT seharvey anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT jjmadan anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT aeades anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT sjpalmer anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT kmrowan anevaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT mosoares evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT njwelton evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT daharrison evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT ppeura evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT mshari evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT seharvey evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT jjmadan evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT aeades evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT sjpalmer evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis AT kmrowan evaluationofthefeasibilitycostandvalueofinformationofamulticentrerandomisedcontrolledtrialofintravenousimmunoglobulinforsepsisseveresepsisandsepticshockincorporatingasystematicreviewmetaanalysisandvalueofinformationanalysis |