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.

Adult patients with febrile neutropenia in a leukaemia stem-cell transplant unit were given an antibiotic regimen that, in part, involved reducing the dose of intravenous (i.v.) ciprofloxacin from 400 to 200 mg every 12 hours before the patients were moved from i.v. to oral (p.o.) ciprofloxacin. The reduction in i.v. dosage and switch to p.o. medication were both made when the patient's condition met certain criteria. In addition to ciprofloxacin, the initial antibiotic regimen consisted of ceflazidime plus vancomycin or tobramycin plus vancomycin. The comparator group consisted of an antibiotic regimen that started in the same way as that described above, but in which no reduction in i.v. dosage was made.

Treatment.

Cost-effectiveness analysis.

The study population comprised high-risk adults with febrile neutropenia. Patients with febrile neutropenia were defined as those having a fever (>38 degrees C) who were either neutropenic (absolute neutrophil count, ANC, <500 cells/mm3) or whose ANC was decreasing, but had not yet fallen to that level, or who were receiving chemotherapeutic regimens that would result in an ANC below that level. High-risk patients were those with a long duration of neutropenia (more than 7 days), a rapid decrease in neutrophil count, leukaemia induction or bone marrow transplantation (BMT), co-morbid medical conditions, bacteraemia or documented infection, or those who were inpatients at the time of fever and neutropenia.

The setting was secondary care (stem-cell transplant unit). The economic study was carried out in Vancouver, Canada.

The dates for effectiveness evidence were not explicitly reported, but can be inferred to have been 1998. The dates to which resource use related were unclear. Some costs were derived from a study published in 1992. The other costs might have been collected in 1998. The price year was 1998.

The effectiveness data were derived from a single study.

The costing was undertaken retrospectively on the same patient sample that provided the effectiveness evidence.

The authors estimated that "a convenience sample of 50 treatment courses/phase would have been adequate" in both groups. However, no power calculations were performed. The sample was selected using random number-generating software. The control group was defined by the 6-month period before the intervention (phase I), while the intervention group was defined by the 6-month period after the intervention (phase II). Before the intervention, the patients received 400-mg i.v. ciprofloxacin every 12 hours. During phase I (control group), 46 treatment courses were begun in 42 febrile neutropenic patients. In phase II (intervention group), 42 treatment courses were begun in 36 patients.

This was a single-centre, non-randomised study that examined patients during their hospital stay. Investigators who were blinded to the patient's treatment group assessed patient outcomes. The duration of follow-up was until discharge.

It appears that the analysis was conducted on the basis of treatment completers only. The primary health outcomes used were cure or improvement, or failure. Cure or improvement was defined as afebrile with complete or incomplete resolution of other signs and symptoms of infection, and no other evidence of infection at the end of ciprofloxacin therapy. Failure was defined as no significant resolution of the signs of infection or intolerance to ciprofloxacin, resulting in its discontinuation.

Microbiological outcomes were also assessed on the basis of eradication, persistence, colonisation, or superinfection. If cultures at the end of therapy were unavailable, eradication was assumed if clinical cure or improvement was obtained.

The frequency of adverse drug reactions (ADRs) was also measured. The likelihood of an association of an ADR with ciprofloxacin was determined on the basis of the following criteria:

known ADR;

temporal relationship, ADR disappeared with dosage reduction or discontinuation of ciprofloxacin;

symptoms could not be explained by any other known condition or predisposition of the patient; and

symptoms reappeared on rechallenge with ciprofloxacin.

An ADR was definite (all five criteria were satisfied), probable (the first four criteria were satisfied), possible (the first three criteria were satisfied), or unlikely-unevaluable.

The two patient groups were shown to be comparable in terms of demographics but there was a difference in health profiles. There were more BMT recipients in the control group, (p=0.02). The duration of therapy was similar between the groups.

There was no statistically significant difference in clinical outcomes between the two treatment groups:

83% of treatment courses in the control group and 81% of the treatment courses in the stepdown group resulted in cure or improvement, (p=0.81);

the eradication rates of bacterial infection were similar between the two treatment courses, (chi-squared 1.0);

there were 12 cases of superinfection, 5 in the control group and 7 in the stepdown group.

There was no significant difference between the two treatment groups in the incidence of ADRs, (Fisher's exact test 0.93).

The authors concluded that the policy of stepping down i.v. ciprofloxacin before switching to p.o. ciprofloxacin, as described in the study, did not result in any difference in health outcomes compared with the practice of not stepping down the i.v. ciprofloxacin.

A decision analytic model was created, using DATA 3.0, to map each treatment arm according to probabilities of stepdown and treatment success or failure.

No summary benefit measure was used in the economic evaluation. Since the authors concluded that the effectiveness results were similar between the groups, a cost-minimisation analysis was conducted.

The perspective of a hospital was adopted in the study. No discounting was carried out since all the costs were incurred during less than 2 years. The costs measured were for i.v. ciprofloxacin, p.o. ciprofloxacin, ancillary antibiotics, laboratory tests, diagnostic tests, procedures, treatments related to infection or adverse events, radiology costs, physician visits and days in the intensive care unit. The labour costs of support staff were not included as the authors assumed they were fixed. The hotel costs and non-physician health professional costs were not calculated as it was assumed that they were common to both treatment courses.

The costs were not broken down into quantities and costs but were given as the cost per treatment course. The drug costs were obtained from the pharmacy drug distribution computer. Preparation and delivery costs were taken from another study conducted by the authors (see Other Publications of Related Interest). The labour and material costs of laboratory tests were taken from the Department of Laboratory Medicine, while diagnostic imaging costs were taken from the Department of Radiology and Image Guided Therapy. The cost of physician visits was taken from the 1998 British Columbia Medical Association's guide to fees. The price year was 1998.

A bootstrap analysis was conducted with 1,000 bootstrap replications. The mean cost-difference between the two treatments was calculated.

No indirect costs were calculated.

Canadian dollars (Can$).

Univariate sensitivity analyses were performed to test the robustness of the model, using probabilities and costs stratified by study phase and clinical outcomes. Also, the probabilities of clinical outcome, ADRs and superinfections were tested. The authors used "plausible" changes in the costs and probabilities.

No summary measure of benefit was calculated, as this was a cost- minimisation analysis.

Overall, the mean cost per treatment course was Can$4,843 in the control group and Can$3,493 in the stepdown group.

The bootstrap analysis showed that 99.8% of the samples showed lower costs for the stepdown courses of treatment.

The costs were calculated during the hospital stay and they included costs of ADRs.

Not relevant as this was a cost-minimisation analysis. The sensitivity analysis showed that no plausible changes in cost or probabilities affected the main results.

The policy of reducing the intravenous (i.v.) dose of ciprofloxacin for adult patients with high-risk febrile neutropenia before moving them to oral (p.o.) ciprofloxacin resulted in lower costs, and did not change the patients' health outcomes.

Selection of comparators

The selection of the comparator (no i.v.-i.v. stepdown programme) was justified by it being current practice in many settings. You should decide if this is a widely used health technology in your own setting.

Validity of estimate of measure of effectiveness:

The effectiveness data were derived from a single study. The basis of the analysis was a non-randomised study with controls that were almost concurrent. The study sample was representative of the study population as all patients satisfying the inclusion criteria were included. The patients were not completely comparable at analysis, as there were more BMT patients in the control group. Hence, confounding factors may have biased the results. In general, the analysis of effectiveness was handled credibly, although there were some aspects that could have been improved. The authors did not allow for the difference in BMT patients in their analysis of the evidence. Although the authors stated that they performed a sensitivity analysis to check that the effectiveness conclusions were not affected by varying crucial parameters, they did not state which crucial parameters were varied or how they were varied. The authors stated that their conclusions might have been affected by an insufficiently large sample size and, therefore, there is a risk of Type II error.

Validity of estimate of measure of benefit:

No summary measure of benefit was used in the economic analysis, which was concerned with comparing costs, having concluded from the effectiveness evidence that both treatments were therapeutically equivalent.

Validity of estimate of costs:

From the cost perspective adopted (i.e. the hospital), most of the costs were included. The authors stated that they did not include hotel costs or nursing costs because these were common to both treatment courses. However, the effectiveness evidence showed differences in the length of hospital stay between the two treatment groups. As the length of stay was longer in the control group, the inclusion of these costs would have supported the authors' conclusions that costs in the control group were higher. The costs were not reported separately from the quantities, although the price of ciprofloxacin and its dosage were given. Although no statistical analysis of the quantities was carried out, it was unclear whether a sensitivity analysis was conducted. The prices were taken from the authors' setting and from published sources. A statistical analysis of the prices was not performed and although a sensitivity analysis was carried out, the authors did not give any details. The price year was 1998.

Other issues:

The authors made appropriate comparisons of their results with the findings from other studies. Although the authors acknowledged that carrying out the study in a single centre could limit its generalisability, they seemed unaware that the lack of a breakdown of the costs into prices and quantities would also limit the generalisability to other settings. The authors did not present their results selectively. They acknowledged that their study could be improved in certain aspects and mentioned, in particular, the small sample size, the lack of comparability and the lack of randomisation.

The authors suggested that the use of i.v. stepdown ciprofloxacin for high-risk, adult patients with febrile neutropenia can reduce costs and it has no deleterious effects on the patients' health outcomes. They suggested that a larger randomised controlled trial should be undertaken to confirm these results. Such a trial should have all the costs clearly displayed and broken down into prices and quantities.

None stated.

Frighetto L, Nickoloff D, Martinusen SM, Mamdani FS, Jewesson PJ. Intravenous-to-oral-stepdown program: four years of experience in a large teaching hospital. Annals of Pharmacotherapy 1992;26:1447-51.