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Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis: a comparative study |
Perini P, Calabrese M, Tiberio M, Ranzato F, Battistin L, Gallo P |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The study compared two treatment protocols for secondary progressive multiple sclerosis (SPMS). These were cyclophosphamide (Cy) and mitoxantrone (Mito).
The Cy therapy protocol was monthly intravenous (i.v.) administration of Cy for 1 year, followed by administration every 2 months during the following year. The dose depended on the leukocyte and lymphocyte counts. It started at 600 mg/m2 and increased by 200 mg/m2 until counts of no less than 2,000/microlitre for leukocytes and 700/microlitre for lymphocytes were obtained. Immediately before Cy, patients were administered uromitexan and 1.5 litres of 0.9% sodium chloride solution to prevent haemorrhagic cystitis.
The Mito therapy regimen was Mito at a dose of 8 mg/m2 every 2 months for 2 years. One litre of 0.9% sodium chloride solution was also administered.
Patients on both regimens received an infusion of 1 g methylprednisolone diluted in 500 mL 0.9% sodium chloride solution and an anti-emetic drug (3 to 9 mg i.v. granisetron).
Economic study type Cost-effectiveness analysis.
Study population The study population comprised patients with MS who were classified as SPMS, and who had continuous progression with relapses (e.g. loss of at least 1 in the Expanded Disability Status Score (EDSS) over the previous 2 years and at least 1 relapse over the last year). The paper reported many exclusion criteria.
Setting The setting was not explicitly reported. The economic study was carried out in Italy.
Dates to which data relate The dates to which the effectiveness and cost data related were not reported. The price year was also not reported.
Link between effectiveness and cost data The costing was undertaken on the same sample of patients as that used in the effectiveness study. It was unclear whether the costing was undertaken prospectively or retrospectively.
Study sample The study did not report the derivation of the sample size. Retrospective power calculations, to assess the power of the study, were not reported. All patients meeting the inclusion criteria underwent bladder echography with quantification of the post-void residual volume and an echo-colour-doppler-cardiography with analysis of the left ventricular ejection fraction. Eligible patients were assigned to treatment groups depending on the results of these examinations. The initial sample comprised 50 patients of whom 25 were allocated to Mito therapy and 25 to Cy therapy. No patients were reported to have been excluded and none refused to participate.
Study design The analysis was based on a prospective, single-centre, non-randomised controlled trial. The patients were followed-up and clinically evaluated every 3 months for 2 years. In addition, all patients underwent magnetic resonance imaging (MRI) at initiation, 1 and 2 years of therapy. The patients and clinicians were not blinded. No patients were lost to follow-up.
Analysis of effectiveness The primary outcomes were the relapse rate and disability as measured by the EDSS. Lesions were also evaluated and were based on the results of the MRI. The secondary outcomes included side effects of the two treatment protocols. It was not reported whether the analysis was conducted on an intention to treat basis. The two groups were demonstrated to be generally comparable in terms of their baseline characteristics. The exception was age at entry to the study: the mean age at study entry was 38.2 years in the Mito group and 42.4 years in the Cy group, (p=0.03).
Effectiveness results For all patients included in the study, it was demonstrated that Mito reduced the relapse rate by 88% (from 2.1 +/- 1.8 before therapy to 0.25 +/- 0.4 during therapy; p=0.001). Cy reduced the relapse rate by 86.4% (from 2.2 +/- 1.9 before therapy to 0.3 +/- 0.5 after therapy; p=0.003).
In the Mito group, the mean EDSS decreased from 5.4 at study entry to 4.6 after 2 years of therapy (p=0.01). In the Cy group, the mean EDSS decreased from 5.7 to 4.8, (p=0.02).
A sub-group analysis was restricted to only those patients who responded to treatment. In the Mito group (14 responders), the mean decrease in EDSS at the end of therapy was -1.7 points, (p=0.0001), and the difference in the relapse rate was 2.6. In the Cy group (17 responders), the mean change in EDSS was -1.3 points, (p=0.0004), and the difference in the relapse rate was 2.5. The differences between responders and all patients treated were not statistically significant.
MRI demonstrated that differences in Gad+ lesions before and after treatment were statistically insignificant for both groups.
Clinical conclusions The authors concluded that both treatment protocols had similar and significant effects in diminishing disease activity and the progression of SPMS with relapses, and demonstrated an acceptable safety profile.
Measure of benefits used in the economic analysis The authors did not derive a summary measure of benefit in the economic analysis. In effect, a cost-consequences analysis was performed.
Direct costs The direct costs included in the analysis were for medications, day hospital (nurse, pharmacist and neurological evaluation) and diagnosis (echo-colour-doppler-cardiography, bladder echography, cystoscopy and cytological urine examination). The sources of the resources used and unit costs were not reported. The costs were reported as the average net cost per patient. Discounting was not performed and the price year was not reported. The costs and the quantities were not reported separately.
Statistical analysis of costs No statistical analysis of the costs or quantities was performed.
Indirect Costs Productivity costs were not included in the analysis.
Sensitivity analysis Since a sensitivity analysis was not performed, the authors did not investigate uncertainty.
Estimated benefits used in the economic analysis See the 'Effectiveness Results' section.
Cost results The average cost per patient was EUR 8,171 in the Mito group and EUR 5,097 in the Cy group.
Synthesis of costs and benefits The costs and benefits were not combined.
Authors' conclusions The cyclophosphamide (Cy) therapy protocol demonstrated a similar effectiveness and safety profile to mitoxantrone (Mito), but was significantly cheaper.
CRD COMMENTARY - Selection of comparators A justification was provided for the technologies compared. The Mito therapy protocol represented the officially approved first-line therapy for relapsing-remitting MS. In contrast, Cy is not approved for MS treatment and, in the authors' setting, is only being used with a patient's informed consent. You should decide if these represent valid comparators in your own setting.
Validity of estimate of measure of effectiveness The analysis was based on a non-randomised controlled trial. This type of study is usually associated with some limitations in view of the lack of random allocation of the patients to the study groups. Thus, some selection bias might have affected the results. The study did not report any power calculations to ensure that the size of the study sample was adequate to detect statistical significant differences. It is therefore not possible to ascertain whether the results obtained were due to the intervention or to chance.
The patients' characteristics were reported in some detail, thus allowing readers to assess the extent to which their own patients are comparable with those in the study. Although the blinding of clinicians and researchers who collected the outcome information should have been possible, and would have helped to minimise potential biases in the data analysis, the possibility was not discussed. It seems that pre- and post-treatment results were compared for each group. However, between-group comparisons were not performed in order to demonstrate the statistical significance of the relative effectiveness of the two treatment protocols.
Validity of estimate of measure of benefit The authors did not derive a summary measure of benefit. In effect, a cost-consequences analysis was performed.
Validity of estimate of costs Although the perspective from which the costing was carried out was not specified, it appears to have been that of the health care provider. However, since the authors reported very limited information on their costing study, it was not possible to determine whether all the relevant cost categories were included in the analysis. Side effects were not accounted for in the economic analysis, and their inclusion could have affected the results. In addition, the sources and values of resources used and of the prices were not reported. These facts will limit the generalisability of the authors' results. Neither statistical nor sensitivity analyses of the costs were performed, which might introduce uncertainty. The price year was not reported and discounting was not conducted, although the costs were incurred during 2 years. Again, such lack of detail will limit the generalisability of the authors' results and their internal validity.
Other issues The authors compared their findings with those from previous studies and discussed methodological differences. The issue of the generalisability of the results to other settings was not explicitly addressed. The results of this study would appear to be valid for a different population to that studied in the other studies. Although the results do not appear to have been presented selectively, between-group comparisons were not performed to reflect the relative effectiveness of the two treatment protocols. The analysis included patients with SPMS and this was reflected in the authors' conclusions. The authors did not report any limitations to their study.
Implications of the study The authors recommend that the Cy protocol should be considered as first-line therapy for patients with SPMS. However, concerns about the validity of the evidence used in the study, as discussed in the commentary above, should be borne in mind when considering this recommendation. Although the authors made no recommendations for further research, the above commentary highlights areas where more robust evidence is necessary.
Bibliographic details Perini P, Calabrese M, Tiberio M, Ranzato F, Battistin L, Gallo P. Mitoxantrone versus cyclophosphamide in secondary-progressive multiple sclerosis: a comparative study. Journal of Neurology 2006; 253(8): 1034-1040 Indexing Status Subject indexing assigned by NLM MeSH Adult; Cyclophosphamide /administration & Drug Administration Schedule; Drug Costs; Female; Humans; Immunosuppressive Agents /administration & Italy; Male; Middle Aged; Mitoxantrone /administration & Multiple Sclerosis, Chronic Progressive /drug therapy /economics; Treatment Outcome; dosage /adverse effects /economics /therapeutic use; dosage /adverse effects /economics /therapeutic use; dosage /adverse effects /economics /therapeutic use AccessionNumber 22006001982 Date bibliographic record published 31/07/2007 Date abstract record published 31/07/2007 |
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