Cost effectiveness of monotherapy and aminoglycoside/ureidopenicillin combination therapy for the treatment of febrile episodes in neutropenic patients Paladino J A, Fong D A, Forrest A, Ramphal R

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 Cephalosporin monotherapy and aminoglycoside/ureidopenicillin combination therapy for the treatment of febrile episodes in neutropenic patients.

Type of intervention Treatment.

Economic study type Cost-effectiveness analysis.

Study population The study population was adult patients with neutropenia.

Setting The study setting was hospital. The economic study was set in the USA.

Dates to which data relate Effectiveness and resource use data were collected from studies published between 1993 and 1998. A blinded pharmacoeconomic investigator assigned resource use data. Cost data were incurred by a reference university-affiliated community hospital and were collected from studies published between 1984 and 1997. The price year was 1997.

Source of effectiveness data Effectiveness data were derived from a review of the literature.

Modelling A decision analytic model was used to determine the cost-effectiveness of the three treatment strategies.

Outcomes assessed in the review The review assessed creatinine clearance, duration of neutropenia and infection, and types and number of causative pathogens.

Study designs and other criteria for inclusion in the review Effectiveness estimates were collected from 3 prospective, randomised trials comparing monotherapy with monotherapy, and from 2 prospective, randomised trials comparing cefepime monotherapy with

Page: 1 / 5 aminoglycoside/ureidopenicillin combination therapy. Inclusion criteria included age greater than 16 years, oral temperature greater than 38 degrees C at least twice during a 24-hour period, absolute neutrophil count (ANC) less than 500 cells/microliter or ANC between 500 and 1000 cells/microliter that was expected to fall below 500 cells/microliter within 48 hours, and diagnosis leading to neutropenia. Patients were excluded for any of the following criteria: history of serious hypersensitivity to , or aminoglycosides, administration of parenteral antibacterials in the previous 24 hours, pregnancy or lactation, severe renal insufficiency, "do not resuscitate" or "no code" status.

Sources searched to identify primary studies Not stated.

Criteria used to ensure the validity of primary studies Blinded consultants assessed clinical outcome parameters.

Methods used to judge relevance and validity, and for extracting data Summary statistics from individual studies were used.

Number of primary studies included Five trials were included in the review.

Methods of combining primary studies The narrative method was used to combine primary studies.

Investigation of differences between primary studies Not stated.

Results of the review The median creatinine clearance (ml/min) was 81 with cefepime monotherapy, 76 with ceftazidime monotherapy, 78 with cefepime combination therapy, and 85 with gentamicin/ureidopenicillin combination therapy.

The median number of days of neutropenia was 8 (1-56) with cefepime monotherapy, 8 (1-44) with ceftazidime monotherapy, 15 (2-85) with cefepime combination therapy, and 12 (1-63) with gentamicin/ureidopenicillin combination therapy.

The median number of days of severe neutropenia was 6 (1-39) with cefepime monotherapy, 6 (1-37) with ceftazidime monotherapy, 10 (1-45) with cefepime combination therapy, and 8 (1-61) with gentamicin/ureidopenicillin combination therapy.

The majority of patients across all treatment groups presented with either fever of unknown origin or bacteraemia. No statistically significant differences in causative pathogens were detected between comparator groups for patients with microbiologically documented infection (MDI). In either comparison, the majority of pathogens were Grampositive . The number of recovered pathogens exceeded the number of patients with MDI due to polymicrobial infections in some patients.

Measure of benefits used in the economic analysis Measures of benefit included clinical response rates, frequency of adverse events, mortality rates, and length of stay. Benefits did not need to be discounted.

Page: 2 / 5 Direct costs Direct costs did not need to be discounted. Quantities and costs were reported separately. Direct costs included drug acquisition costs, antibacterial-related direct costs, such as antibacterial acquisition, preparation and administration, and additional medications and procedures used to manage therapeutic failures and adverse events, and the cost of hospital stay. The quantity/cost boundary adopted was that of the hospital. The estimation of quantities and costs was based on actual data. Cost data were incurred by a reference university-affiliated community hospital and were collected from studies published between 1984 and 1997. The price year was 1997.

Statistical analysis of costs The Kruskal-Wallis 1-way analysis of variance test was used to conduct between-treatment comparisons.

Indirect Costs Indirect costs were not included.

Currency US dollars ($).

Sensitivity analysis Sensitivity analyses were conducted on drug acquisition costs, hospital bed costs, probability of clinical success, and the effect of mortality.

Estimated benefits used in the economic analysis No statistically significant differences in clinical response rates, frequency of adverse events, mortality rates or length of stay could be detected between treatment groups for either component of the study. The clinical success rates for the monotherapy comparisons were 38% for cefepime-treated patients and 40% for ceftazidime-treated patients. Success rates for the monotherapy versus combination therapy comparison were 37% and 36% for cefepime- and gentamicin/ureidopenicillin-treated patients. The majority of adverse events consisted of rash and gastrointestinal disturbances of moderate severity.

Cost results Median costs for patients enrolled in the monotherapy trials amounted to $7,849 (range: 3,304 - 53,538) for cefepime- treated patients and $7,788 (range: 3,172 - 35,866) for ceftazidime-treated patients, (p=0.884).

Median costs for the monotherapy versus combination therapy comparison amounted to $9,780 (range: 3,289 - 23,454) for cefepime-treated patients and $10,159 (range: 3,512 - 27,674) for gentamicin/ureidopenicillin-treated patients, (p=0.372).

Synthesis of costs and benefits The confidence intervals for differences in cost-effectiveness ratios (cefepime minus comparator) for both the monotherapy comparison (-$4,137 to +$4,881) and the combination therapy comparison (-$17,650 to +$9,522) include a value of zero, confirming the lack of statistically significant differences in cost-effectiveness between cefepime and either ceftazidime monotherapy or gentamicin/ureidopenicillin combination therapy. However, the confidence intervals for differences in cost-effectiveness ratios for the combination therapy comparison clearly favoured cefepime monotherapy. Sensitivity analysis revealed that monotherapy can be cost-effective compared with combination therapy in many situations.

Authors' conclusions

Page: 3 / 5 There were no economic differences between the three regimens tested. Thus, drug cost should not be a deciding factor when choosing antibacterial therapy for the treatment of febrile episodes in adult patients with neutropenia.

CRD COMMENTARY - Selection of comparators A justification was given for the comparators used namely that it was a currently employed strategy. You, as a user of the database, should decide if these health technologies are relevant to your setting.

Validity of estimate of measure of benefit The authors did not state that a systematic review of the literature had been undertaken. More information about the design of the review and the method of combining primary effectiveness estimates could have been reported. Estimation of benefits was obtained directly from the effectiveness analysis.

Validity of estimate of costs Good features of the cost analysis were that all relevant cost categories were included, sensitivity analyses were conducted on costs and quantities, quantities and costs were reported separately, and the price year was reported. However, it was unclear whether charges were used to proxy prices.

Other issues The authors did make appropriate comparisons of their findings with those from other studies and the issue of generalisability to other settings was addressed. The authors did not present their results selectively. The study considered patients with neutropenia and this was reflected in the authors' conclusions. The analysis used differences in average cost-effectiveness ratios, which is methodologically inferior to using incremental cost-effectiveness ratios. The authors noted that costs associated with the determination of antibacterial concentrations were not accounted for due to lack of data. Thus, this analysis undercosts the combination regimen. In addition, the unquantified costs of inconvenience associated with combination therapy, as well as the more frequent administration schedules of ureidopenicillins, may be important to patients and caregivers.

Implications of the study Monotherapy can be cost-effective compared with combination therapy in many situations. Other issues that require future investigation include the cost-effectiveness of a 1g dose or twice-daily administration of cefepime monotherapy, as well as the relative cost-effectiveness of monotherapy and / monotherapy.

Source of funding Funded in part by an unrestricted grant from Bristol-Myers Squibb Company.

Bibliographic details Paladino J A, Fong D A, Forrest A, Ramphal R. Cost effectiveness of cephalosporin monotherapy and aminoglycoside/ureidopenicillin combination therapy for the treatment of febrile episodes in neutropenic patients. PharmacoEconomics 2000; 18(4): 369-381

PubMedID 15344305

Indexing Status Subject indexing assigned by NLM

MeSH Aminoglycosides /administration & dosage; Cephalosporins /therapeutic use; Cost-Benefit Analysis; Drug Therapy,

Page: 4 / 5 Combination /therapeutic use; Fever /drug therapy; Health Care Costs; Humans; Neutropenia /complications; Penicillins /administration & dosage; Retrospective Studies

AccessionNumber 22000008302

Date bibliographic record published 31/08/2001

Date abstract record published 31/08/2001

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