Structural neuroimaging in psychosis: a systematic review and economic evaluation.

OBJECTIVES: To establish the clinical effectiveness and cost-effectiveness of structural neuroimaging [structural magnetic resonance imaging (MRI) or computed tomography (CT) scanning] for all patients with psychosis, particularly a first episode of psychosis, relative to the current UK practice of selective screening only where it is clinically indicated. DATA SOURCES: Major electronic databases were searched from inception to November 2006. REVIEW METHODS: A systematic review of studies reporting the additional diagnostic benefit of structural MRI, CT or combinations of these in patients with psychosis was conducted. The economic assessment consisted of a systematic review of economic evaluations and the development of a threshold analysis to predict the gain in quality-adjusted life-years (QALYs) required to make neuroimaging cost-effective at commonly accepted threshold levels (20,000 pounds and 30,000 pounds per QALY). Sensitivity analyses of several parameters including prevalence of psychosis were performed. RESULTS: The systematic review included 24 studies of a diagnostic before-after type of design evaluating the clinical benefit of CT, structural MRI or combinations in treatment-naive, first-episode or unspecified psychotic patients, including one in schizophrenia patients resistant to treatment. Also included was a review of published case reports of misidentification syndromes. Almost all evidence was in patients aged less than 65 years. In most studies, structural neuroimaging identified very little that would influence patient management that was not suspected based on a medical history and/or physical examination and there were more incidental findings. In the four MRI studies, approximately 5% of patients had findings that would influence clinical management, whereas in the CT studies, approximately 0.5% of patients had these findings. The review of misidentification syndromes found that 25% of CT scans affected clinical management, but this may have been a selected and therefore unrepresentative sample. A threshold analysis with a 1-year time horizon was undertaken. This combined the incremental cost of routine scanning with a threshold cost per QALY value of 20,000 pounds and 30,000 pounds to predict the QoL gain required to meet these threshold values. Routine scanning versus selective scanning appears to produce different results for MRI and CT. With MRI scanning the incremental cost is positive, ranging from 37 pounds to 150 pounds; however, when scanning routinely using CT, the result is cost saving, ranging from 7 pounds to 108 pounds with the assumption of a 1% prevalence rate of tumours/cysts or other organic causes amenable to treatment. This means that for the intervention to be viewed as cost-effective, the QALY gain necessary for MRI scanning is 0.002-0.007 and with CT scanning the QALY loss that can be tolerated is between 0.0003 and 0.0054 using a 20,000 pounds threshold value. These estimates were subjected to sensitivity analysis. With a 3-month time delay, MRI remains cost-incurring with a small gain in QoL required for the intervention to be cost-effective; routine scanning with CT remains cost-saving. When the sensitivity of CT is varied to 50%, routine scanning is both cost-incurring or cost-saving depending on the scenario. Finally, the results have been shown to be sensitive to the assumed prevalence rate of brain tumours in a psychotic population. CONCLUSIONS: The evidence to date suggests that if screening with structural neuroimaging was implemented in all patients presenting with psychotic symptoms, little would be found to affect clinical management in addition to that suspected by a full clinical history and neurological examination. From an economic perspective, the outcome is not clear. The strategy of neuroimaging for all is either cost-incurring or cost-saving (dependent upon whether MRI or CT is used) if the prevalence of organic causes is around 1%. However, these values are nested within a number of assumptions, and so have to be interpreted with caution. The main research priorities are to monitor the current use of structural neuroimaging in psychosis in the NHS to identify clinical triggers to its current use and subsequent outcomes; to undertake well-conducted diagnostic before-and-after studies on representative populations to determine the clinical utility of structural neuroimaging in this patient group, and to determine whether the most appropriate structural imaging modality in psychosis should be CT or MRI.

A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

OBJECTIVES: To review the clinical and cost-effectiveness of basiliximab, daclizumab, tacrolimus, mycophenolate mofetil (MMF), mycophenolate sodium (MPS) and sirolimus as possible immunosuppressive therapies for renal transplantation in children. DATA SOURCES: Electronic databases were searched up to November 2004. REVIEW METHODS: Data from selected studies were extracted and quality assessed. An economic model [Birmingham Sensitivity Analysis paediatrics (BSAp)] was produced based on an adaptation of a model previously developed for the assessment of the cost-effectiveness of immunosuppressants in adults following renal transplant. RESULTS: For the addition of basiliximab, one unpublished paediatric randomised control trial (RCT), reported that the addition of basiliximab to tacrolimus-based triple therapy (BTAS) failed to significantly improve 6-month biopsy-proven acute rejection (BPAR), graft function, graft loss and all-cause mortality. No significant difference between groups was seen in 6-month or 1-year or longer graft loss, all-cause mortality and side-effects. In a meta-analysis of adult RCTs, the addition of basiliximab to a ciclosporin, azathioprine and steroid regimen (CAS) significantly reduced short-term BPAR. There was no significant difference in short- or long-term graft loss, all-cause mortality or side-effects. One adult RCT was included for the addition of daclizumab to CAS, which reported reduced 1-year BPAR, although no difference between groups was seen in either 1- or 3-year graft loss, all-cause mortality and side-effects. For tacrolimus versus ciclosporin, one unpublished paediatric RCT found that a regimen of tacrolimus, azathioprine and a steroid (TAS) reduced 6-month BPAR and improved graft function [glomerular filtration rate (GFR)] compared with CAS. This improvement in BPAR with tacrolimus was as shown in the meta-analysis of adult RCTs. There was evidence, particularly in children, that in comparison with ciclosporin, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. The total level of withdrawal in children was reduced in children receiving tacrolimus. Adult RCTs showed an increase in post-transplant diabetes mellitus with tacrolimus. For MMF versus azathioprine, a meta-analysis of adult RCTs showed MMF [regimen of ciclosporin, MMF and a steroid (CMS)] to reduce 1-year BPAR compared with azathioprine (CAS). There was evidence, particularly in children, that in comparison with azathioprine, tacrolimus may reduce long-term graft loss, although there is no benefit on total mortality. There was an increase in the level of cytomegalovirus infection with MMF, although the overall level of withdrawal due to adverse events was not different to that of azathioprine-treated adults. No study comparing MPS with azathioprine (CAS) was identified. In an adult RCT comparing MMF with MPS, there was no significant difference between groups in 1-year efficacy or side-effects. One unpublished paediatric RCT assessed the addition of sirolimus to CAS. BPAR, graft loss and all-cause mortality were not reported. In two adult RCTs, compared with azathioprine, sirolimus reduced 1-year BPAR, reduced graft function (as assessed by an increased serum creatinine) and increased the level of hyperlipidaemia. No significant differences were seen in other efficacy and side-effect outcomes. On an adult RCT comparing sirolimus with ciclosporin, there were no significant differences between groups in 1-year efficacy or side-effects with the exception of an increased level of hyperlipidaemia with sirolimus substitution. Both the assessment group and drug companies assessed the cost-effectiveness of the newer renal immunosuppressants currently licensed in children using an adaptation (BSAp) of the Birmingham Sensitivity Analysis (BSA) model. This model is based on a 10-year extrapolation of 1-year BPAR results sourced from paediatric RCTs or adult RCTs (where paediatric RCTs were not available). The addition of basiliximab and that of daclizumab to CAS was found to increase quality-adjusted life-years (QALYs) and decreased overall costs, a finding that was robust to sensitivity analyses. The incremental cost-effectiveness ratio (ICER) of replacing ciclosporin with tacrolimus was highly sensitive to the selection of the hazard ratio for graft loss from acute rejection, dialysis costs and the incorporation (or not) of side-effects. The ICERs for tacrolimus versus ciclosporin ranged from about 46,000 pounds/QALY to about 146,000 pounds/QALY. Although sensitive to varying the hazard ratio for graft loss with acute rejection, the ICER for replacing azathioprine with MMF remained in excess of 55,000 pounds/QALY. CONCLUSIONS: In general, compared with a regimen of ciclosporin, azathioprine and steroid, the newer immunosuppressive agents consistently reduced the incidence of short-term biopsy-proven acute rejection. However, evidence of the impact on side-effects, long-term graft loss, compliance and overall health-related quality of life is limited. Cost-effectiveness was estimated based on the relationship between short-term acute rejection levels from RCTs and long-term graft loss. Both the addition of daclizumab and that of basiliximab were found to be dominant strategies, that is, regarding cost savings and increased QALYs. The incremental cost-effectiveness of tacrolimus relative to ciclosporin was highly sensitive to key model parameter values and therefore may well be a cost-effective strategy. The incremental cost-effectiveness of MMF compared with azathioprine, although also sensitive to model parameter, was unattractive. There is a particular need for RCTs to assess the use of MMF, MPS and daclizumab for renal transplantation in children where no such evidence currently exists. Future comparative studies need to report not only on the impact of the newer immunosuppressants on short- and long-term clinical outcomes but also on side-effects, compliance, healthcare resource, costs and health-related quality of life.