The clinical effectiveness and cost-effectiveness of primary stroke prevention in children with sickle cell disease: a systematic review and economic evaluation.

BACKGROUND: Sickle cell disease (SCD) is a recessive genetic blood disorder, caused by a mutation in the ß-globin gene. For children with SCD, the risk of stroke is estimated to be up to 250 times higher than in the general childhood population. Transcranial Doppler (TCD) ultrasonography is a non-invasive technique which measures local blood velocity in the proximal portions of large intracranial arteries. Screening with TCD ultrasonography identifies individuals with high cerebral blood velocity; these children are at the highest risk of stroke. A number of primary stroke prevention strategies are currently used in clinical practice in the UK including blood transfusion, treatment with hydroxycarbamide and bone marrow transplantation (BMT). No reviews have yet assessed the clinical effectiveness and cost effectiveness of primary stroke prevention strategies in children with SCD identified to be at high risk of stroke using TCD ultrasonography. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of primary stroke prevention treatments for children with SCD who are identified (using TCD ultrasonography) to be at high risk of stroke. DATA SOURCES: Electronic databases were searched from inception up to May 2011, including the Cochrane Database of Systematic Reviews (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstracts of Reviews of Effects (DARE), EMBASE, the Health Technology Assessment (HTA) database, ISI Web of Science Proceedings, ISI Web of Science Citation Index, the NHS Economic Evaluation Database (NHS EED) and MEDLINE. REVIEW METHODS: The assessment was conducted according to accepted procedures for conducting and reporting systematic reviews and economic evaluations. A de novo Markov model was developed to determine the cost-effectiveness of TCD ultrasonography and blood transfusion, where clinically appropriate, in patients with SCD. RESULTS: Two randomised controlled trials met the inclusion criteria involving a study population of 209 participants. One compared blood transfusion with standard care for children who are identified as being at high risk of stroke using TCD ultrasonography. In this trial, one patient in the transfusion group had a stroke (1/63) compared with 11 children in the standard care group (11/67). The other trial assessed the impact of halting chronic transfusion in patients with SCD. Sixteen patients in the transfusion-halted group had an event (16/41) (two patients experienced stroke and 14 reverted to abnormal TCD velocity); there were no events in the continued-transfusion group (0/38). No meta-analyses of these trials were undertaken. No relevant economic evaluations were identified for inclusion in the review. The de novo modelling suggests that blood transfusions plus TCD scans (compared with just TCD scans) for patients with SCD at high risk of stroke, aged ≥ 2 years, may be good value for money. The intervention has an incremental cost-effectiveness ratio of £24,075 per quality-adjusted life-year gained, and helps avoid 68 strokes over the lifetime of a population of 1000 patients. The intervention costs an additional £13,751 per patient and generates 0.6 extra years of life in full health per patient. The data available for the economic analysis are limited. Sensitivity analyses and validation against existing data and expert opinion provide some reassurance that the conclusion of the model is reliable but further research is required to validate these findings. LIMITATIONS: The main limitations relate to the availability of published clinical data; no completed randomised controlled trials were identified which evaluated the efficacy of either BMT or hydroxycarbamide for primary stroke prevention. Both the clinical and cost data available for use in the economic analysis are limited. Sensitivity analyses and validation against existing data and expert opinion provide some reassurance that the conclusions of the model are reliable, but further research is required to validate these findings. CONCLUSIONS: The use of TCD ultrasonography to identify children at high risk of stroke, and treating these children with prophylactic blood transfusions, appears to be both clinically effective and cost-effective compared with TCD ultrasonography only. However, given the limitations in the data available, further research is required to verify this conclusion. Several research recommendations can be proposed from this review. Clinically, more research is needed to assess the effects and optimal duration of long-term blood transfusion and the potential role of hydroxycarbamide in primary stroke prevention. From an economics perspective, further research is required to generate more robust data on which to base estimates of cost-effectiveness or against which model outputs can be calibrated. More data are required to explain how utility weights vary with age, transfusions and strokes. Research is also needed around the cost of paediatric stroke in the UK. STUDY REGISTRATION: PROSPERO CRD42011001496. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses.

BACKGROUND: Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). OBJECTIVE: This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. DATA SOURCES: Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. REVIEW METHODS: A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. RESULTS: Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. LIMITATIONS: Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. CONCLUSIONS: From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. FUNDING: The Health Technology Assessment Programme of the National Institute for Health Research.

[Dopamine receptor agonists in treatment of outpatient patients with Parkinson's disease]. / Opyt ispol'zovaniia agonistov dofaminovykh retseptorov v ambulatornom lechenii bolezni Parkinsona.

The paper summarized an experience of pronoran (piribedil) treatment of 516 patients with Parkinson's disease (primary parkinsonism) conducted in the district outpatient clinics of 7 Moscow administrative areas. In 84 cases, the medication was used as a monotherapy and in 432--in combination with levodopa-contained drug madopar. An improvement of patient's state, with reducing of bradikinesia, tremor and rigidity, was achieved in 73.0 +/- 20.4% of the patients. Combined therapy allowed decreasing of madopar dosage in 58.5 +/- 16.7% of the patients. Pronoran (piribedil) is well tolerated. The authors recommend it for the treatment of outpatients with Parkinson's disease.