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.

The use of standardised alanyl-glutamine dipeptide (AGD), 30 g daily, for the parenteral nutrition of autologous transplant patients.

Other: Supportive care.

Cost-effectiveness analysis.

The study population comprised autologous transplant patients. The inclusion criteria were a peripheral blood progenitor cell (PBPC) collection of at least 1 x 10^6/kg CD34+ cells (with or without supplemental bone marrow), adequate organ function, and any conditioning regimen other than paclitaxel with carboplatin that was used for ovarian cancer patients in the OVCAT trial.

The setting was a hospital. The economic study was conducted in the Czech Republic.

The dates during which the effectiveness and resource use data were gathered were not reported. The price year was 2000.

The effectiveness evidence was derived from a single study.

The costing was conducted prospectively on the same sample of patients as that used in the effectiveness study.

Power calculations were not formally conducted. However, on the basis of published studies on allogeneic transplant patients, it was estimated that the sample considered in the study could show at least a trend towards better results in the glutamine group. A sample of 40 consecutive patients was identified, of which 21 received 30 g AGD (containing 20 g of glutamine) and 19 received an isonitrogenous aminoacid solution (placebo). The mean age of the AGD group was 49 (+/- 12) years and 66% were men. The mean age of the placebo group was 42 (+/- 14) years and 58% were men.

This was a prospective, randomised, double-blind, placebo-controlled clinical trial. It was not stated whether it was conducted in a single centre. Randomisation was based on a random-number method in the hospital pharmacy and was stratified according to the patients' diagnosis (i.e. myeloma patients versus other patients). Only the hospital pharmacist was aware of the groups to which the patients were allocated. Other investigators and patients were blinded to the treatment delivered. The solutions were administered for 8 hours daily from day 1+ to day 14+ after stem cell infusion, or to discharge from hospital. The median length of follow-up was 24 months. No loss to follow-up appears to have been observed.

The analysis of the clinical study was conducted on an intention to treat basis. The outcome measures were clinical results, mucositis measures, immunological parameters (lymphocyte sub- populations and immunoglobulin levels), the number of patients transferred to the intensive care unit (ICU), relapse rate, and survival (estimated using Kaplan-Meier methods.

The clinical results covered:

absolute neutrophil count;

days of platelets;

the number of red cell and platelet concentrates;

febrile days;

days on antibiotics, vancomycin, amphotericin-B, opioids, growth factors, and total parenteral nutrition (TPN);

post-transplant hospitalisation; and

oral energy intake in days +1 to +10.

The mucositis measures comprised:

diarrhoea;

the number of days with mucositis; and

the peak oral mucositis score, which was assessed using the Nebraska Oral Assessment Score.

The outcome measures were also estimated after excluding several sub-groups of patients. More specifically, patients in double-transplant programmes, myeloma patients, and patients with multiple sclerosis. The study groups were comparable at baseline in their demographic and clinical characteristics. However, myeloma patients were older and received less CD34+ cells than other patients.

The clinical results were generally not significantly different between the groups. There were two exceptions, days on vancomycin and days on opioids. The number of days on vancomycin was 3.6 (+/- 5.3) in the AGD group and 0.8 (+/- 1.8) in the placebo group, (p=0.03). The number of days on opioids was 3.5 (+/- 4.2) in the AGD group and 1.2 (+/- 2.2) in the placebo group, (p=0.04).

The immunological parameters were comparable.

Among mucositis measures, the number of days of diarrhoea was 3.3 (+/- 4) in the AGD group and 4.3 (+/- 3.3) in the placebo group, (p=0.03). The number of days of severe oral mucositis was 4 (+/- 4.7) in the AGD group and 1.4 (+/- 2.3) in the placebo group, (p=0.04).

Three patients were transferred to the ICU, 2 from the AGD group and 1 from the placebo group.

After follow-up, 3 placebo patients and 10 AGD patients had relapsed.

One placebo patient and 7 AGD patients died.

These differences were statistically significant for relapse-free survival and were generally corroborated in the sub-group analysis.

The effectiveness analysis showed that AGD only resulted in fewer days with diarrhoea. Other outcome measures associated with AGD were either comparable to or worse than those in placebo patients.

The health outcomes were left disaggregated and no summary benefit measure was used in the economic analysis. In effect, a cost-consequences analysis was conducted.

Discounting was not relevant since the costs were not incurred for more than 2 years. The unit costs and the quantities of resources used were not presented separately. The health services included in the economic evaluation were antibiotics, TPN, blood products and growth factors. Other costs were not included in the analysis because they were the same for all patients. The costs associated with stay in the ICU were not included. The cost/resource boundary of the hospital appears to have been adopted. Resource use was estimated using actual data derived from the sample of patients involved in the effectiveness analysis. The costs came from product distributors. The price year was 2000.

Standard statistical analyses were conducted to test the statistical significance of differences in the costs. The costs were presented as mean values with standard deviations.

The indirect costs were not considered.

The costs were estimated in Czech crowns and then converted into Euros. The conversion rate was 1 Euro = 30 Czech crowns.

Sensitivity analyses were not conducted.

See the 'Effectiveness Results' section.

The costs of antibiotics were Euro 628 (+/- 773) with AGD and Euro 223 (+/- 242) with placebo, (p=0.03).

The costs of TPN (excluding AGD) were Euro 97 (+/- 140) with AGD and Euro 91 (+/- 122) with placebo, (p non significant).

The costs of blood products were Euro 873 (+/- 440) with AGD and Euro 767 (+/- 185) with placebo, (p non significant).

The total costs of supportive care were Euro 2,960 (+/- 1,694) with AGD and Euro 1,578 (+/- 662) with placebo, (p=0.002).

Similar cost differences were observed in the sub-group analysis.

A synthesis of the costs and benefits was not relevant since, in effect, a cost-consequences analysis was conducted.

The use of alanyl-glutamine dipeptide (AGD) for the supportive care of autologous transplant patients did not result in improvements in any of the clinical and economic parameters, with the exception of fewer days of diarrhoea. On the contrary, worst clinical outcomes and higher costs were observed.

The rationale for the choice of the comparator was clear. Placebo was selected because the aim of the analysis was to assess the active value of adding glutamine to standard parenteral nutrition. You should decide whether this is a valid comparator in your own setting.

The analysis of effectiveness was based on a clinical trial, which was appropriate for the study question. The internal validity was ensured by several factors. For example, the stratified randomisation, the use of intention to treat as the basis for the analysis of the clinical study, the baseline comparability of the study groups, and double-blinding. Further, power calculations were conducted, although not formally, to detect at least some trends in differences between the groups. The length of follow-up was appropriate. However, the method used to select the sample selection was unclear. Details on the centres in which the study was conducted were not provided. The authors acknowledged that their study sample was quite heterogeneous, but the use of a sub- group analysis further enhanced the robustness of the analysis.

No summary benefit measure was used in the analysis because, in effect, a cost-consequences analysis was conducted.

The perspective adopted in the study was not explicitly stated, but it could have been that of the hospital. The authors justified their exclusion of some categories of costs. A breakdown of the cost items was provided, but information on resource usage and the unit costs was not reported. No sensitivity analyses were carried out and the costs were specific to the study setting. Some statistical tests were conducted when the total costs were compared. The price year was reported, which makes reflation exercises in other settings easy. The source of the data was unclear.

The authors reported the conclusions reached in other published studies. They stated that, in some of the few studies with positive results, there was, in fact, no statistically significant benefit of using AGD. The issue of the generalisability of the study groups was not addressed and sensitivity analyses were not carried out. This adversely affects the external validity of the analysis. The authors discussed some potential reasons for the failure of the study to show beneficial effects of AGD, one of these being the small sample size. However, it was noted that a larger sample would have presumably confirmed the significantly worse outcomes associated with AGD.

The study results suggested that the available data do not support the use of AGD for the parenteral nutrition of autologous transplant patients. The authors suggested that a large, multi- centre, prospective clinical trial in a homogeneous group of patients should be carried out to corroborate the clinical and economic findings of the current analysis.

Supported by grant IGA 5502/3 from the Czech Ministry of Health.

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Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double-blind placebo controlled randomised trial. Gut 2001;48:28-33.

Vahdat L, Papadopoulos K, Lange D, et al. Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clinical Cancer Research 2001;7:1192-7.