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Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin in the treatment of intra-abdominal infections |
Walters D J, Solomkin J S, Paladino J A |
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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 Intravenous (IV) and oral antibacterial drugs in the treatment of intra-abdominal infections.
Economic study type Cost-effectiveness analysis.
Study population Patients aged 18 or over with intra-abdominal infections. Patients were excluded if they had any of the following factors: an Acute Physiology and Chronic Health Evaluation (APACHE) II score greater than 30; the patient was not expected to survive longer than 48 hours; if acute renal insufficiency (dialysis, or serum creatinine level greater than or equal to 2.5 mg/dl after volume resuscitation); if the patient had pre-existing ascites with spontaneous bacterial peritonitis; if the patient had diffuse necrotising pancreatitis or a neutrophil count lower than 1000 cells/mm^3; if the patient had anaphylactoid reactions to fluoroquinolone or beta-lactam antimicrobials; pregnant or nursing women; traumatic perforation of less than 12 hours; duodenal ulcer perforations of less than 24 hours.
Setting Hospital. The economic study was carried out in Canada and the USA.
Dates to which data relate Effectiveness and resource use data corresponded to the subjects recruited to the study between September 1990 and March 1993. The price year was 1996.
Source of effectiveness data Effectiveness data were derived from a single study.
Link between effectiveness and cost data Costing was retrospectively performed on a large sub-sample of the intention to treat patient sample used in the effectiveness analysis.
Study sample Power calculations were used to determine the sample size: based on 10% maximum tolerable difference in bacterial eradication rate, two-tailed alpha of 0.05, a sample size of 150 subjects per study group was required assuming a 90% bacterial eradication rate to achieve an 80% power level. The study initially included a total of 691 patients. Of these, 20 did not receive the study drug and were excluded, while the remainder (n=671) were regarded as the intention to treat study population and were randomly assigned to one of the three study groups. The distribution of intention to treat patients among the three study groups was not reported.
The distribution of efficacy-valid patients (those undergoing operative or percutaneous procedures with identification of an intra-abdominal process, having cultures from abdomen or blood cultures positive for pathogenic bacteria, and survival more than 48 hours) were as follows:
111 subjects in the CIP/MTZ IV group with a mean (SD) age of 49.7 (19.7) years, 57 of whom continued the same treatment after days 3 to 8 while 54 were switched to receiving the same treatment plus sequential placebo PO;
106 in the CIP/MTZ IV/PO group with a mean (SD) age of 52.3 (18.3) years, 60 of whom continued with IV treatment while 46 were switched to receiving sequential CIP/MTZ PO with placebo IV;
113 in the IMI IV group with a mean (SD) age of 56.1 (20.2) years, 58 of whom continued with IV treatment while 55 were switched to receiving sequential placebo PO.
Economically evaluable patients (those undergoing an operative or percutaneous procedure with identification of an intra-abdominal process) consisted of 446 patients the distribution of whom was as follows:
149 subjects in the CIP/MTZ IV group, 88 of whom continued the same active IV treatment (IV(A)) after days 3 to 8 while 61 were switched to receiving the same treatment plus sequential placebo PO (PO(P));
136 in the CIP/MTZ IV/PO group, 85 of whom continued with IV(A) only while 51 were switched to IV (P)/PO(A);
161 in the IMI IV group, 97 of whom continued with IV(A) only while 64 were switched to IV(A)/PO(P).
Study design This was a double-blind, randomized, controlled trial, carried out in 22 centres. The duration of the follow-up was 4 to 6 weeks for the valid population and for other patients it was reported to be variable. Stratification of patients was performed based on APACHE II scores lower than 20 or 20 or more.
Analysis of effectiveness The principle used in the analysis of effectiveness was both intention to treat and efficacy-valid population. The clinical outcome measure was the success rate. The intention to treat study groups were comparable in terms of sex, race, etiology of infection, whether the infection was hospital acquired, the presence of accompanying disease, and the administration of previous, concomitant, and post-therapy antimicrobials as well as age, APACHE II score, and duration of therapy. The valid population were not comparable in terms of the last three variables. Economically evaluable study groups were comparable in terms of all related variables except for age.
Effectiveness results In terms of intention to treat, the CIP/MTZ IV group had a success rate of 82% versus 84% in the CIP/MTZ IV/PO group and 82% in the IMI IV group. For valid populations, the corresponding values were 84%, 86%, and 81%. For the economically evaluable population, the success rates for the patients able to receive oral therapy were:
98% for the group receiving CIP/MTZ IV/PO, IV(P)/PO(A);
93% for CIP/MTZ IV, IV(A)/PO(P);
95% for IMI IV, IV(A)/PO(P); and
94% for CIP/MTZ IV, IV(A)/PO(P) + IMI IV, IV(A)/PO(P).
The success rates for the patients not able to receive oral therapy were:
75% for the groups receiving IMI IV, IV(A) only;
78% for CIP/MTZ IV/PO, IV(A) only;
76% for CIP/MTZ IV, IV (A) only; and
77% for CIP/MTZ IV/PO, IV(A) only + CIP/MTZ IV, IV (A) only.
The outcome differences between the study groups with patients able to receive oral medications were not statistically significant. The same premise was true for patients unable to receive oral medications.
Clinical conclusions These results demonstrate statistical equivalence between CIP/MTZ IV and IMI IV in both the intention to treat and valid populations. Conversion to oral therapy with CIP/MTZ appears as effective as continued intravenous therapy in patients able to tolerate oral feedings.
Measure of benefits used in the economic analysis The benefit measure was success rate.
Direct costs Costs were not discounted. Quantities were reported separately from the costs in terms of mean duration of drug therapy and length of stay (LOS). Cost components were reported separately. Cost analysis covered the costs of antibacterials, preparation and administration, adverse event treatment, laboratory tests, operations and other therapeutic procedures, diagnostic and radiological procedures, therapeutic adjuncts, subsequent procedures, and hospital beds. The perspective adopted in the cost analysis was that of a hospital provider. The source of resource use data was the patient records (case report forms) in a database created for resource utilization. The sources of cost data were 2 reference hospitals in Canada and two in the USA. When only charge data were available, cost-to-charge ratios were used. 1996 price data were used.
Statistical analysis of costs Kruskal-Wallis analysis of variance was utilized to compare cost outcomes.
Currency US ($) and Canadian (Can$) dollars.
Sensitivity analysis One-way sensitivity analyses were conducted on various acquisition prices, hospital per diem, and the probability of success. Threshold values were identified for sensitive parameters.
Estimated benefits used in the economic analysis Success rates were already reported in the effectiveness result section.
Cost results The mean (SD) cost (in US dollars) for the patients able to receive oral therapy were:
$7,678 (2,959) for CIP/MTZ IV/PO, IV(P)/PO(A);
$8,422 (3,046) for CIP/MTZ IV, IV(A)/PO(P);
$9,109 (4,299) for IMI IV, IV(A)/PO(P); and
$8,774 (3,742) for CIP/MTZ IV, IV(A)/PO(P) + IMI IV, IV(A)/PO(P);
p=0.029 for the comparison between the first and fourth values.
The values for patients not able to receive oral therapy were:
$12,418 (6,357) for IMI IV, IV(A) only;
$11,903 (6,889) for CIP/MTZ IV/PO, IV(A) only;
$12,523 (6,770) for CIP/MTZ IV, IV (A) only; and
$12,219 (941) for CIP/MTZ IV/PO, IV(A) only + CIP/MTZ IV, IV (A) only (p=0.26).
Synthesis of costs and benefits The mean cost per patient treated successfully was calculated as the measure of cost-effectiveness and produced the following values for patients able to receive oral therapy:
$7,835 for CIP/MTZ IV/PO, IV(P)/PO(A);
$9,056 for CIP/MTZ IV, IV(A)/PO(P);
$9,588 for IMI IV, IV(A)/PO(P); and
$9,334 for CIP/MTZ IV, IV(A)/PO(P) + IMI IV, IV(A)/PO(P).
The corresponding values for patients unable to receive oral therapy were:
$16 557 for IMI IV, IV(A) only;
$15 260 for CIP/MTZ IV/PO, IV(A) only;
$16 478 for CIP/MTZ IV, IV (A) only; and
$15 869 for CIP/MTZ IV/PO, IV(A) only + CIP/MTZ IV, IV (A) only.
An incremental analysis was not possible due to statistically insignificant clinical outcome differences among the study groups. The sensitivity analyses established the relative robustness of the favourable results to a switch from IV to oral therapy.
Authors' conclusions In patients able to receive oral therapy, sequential IV to oral treatment with ciprofloxacin plus metronidazole was cost-effective compared with full IV courses of ciprofloxacin plus metronidazole or imipenem-cilastatin. In patients unable to receive oral therapy, no difference in mean cost was found between IV imipenem-cilastatin or IV ciprofloxacin plus IV metronidazole.
CRD COMMENTARY - Selection of comparators A justification was given for the choice of the comparator (IMI IV). It was an agent widely used in clinical trials.
Validity of estimate of measure of benefit The internal validity of the estimate of benefit measure is likely to be high due to the use of a study with a randomized design plus intention to treat analysis as the source of data on effectiveness measures.
Validity of estimate of costs Adequate details of methods of cost estimation were given. The cost data were derived, where necessary, from a cost-to-charge ratio which increases the generalisability of the results to other settings.
Other issues The authors' conclusion seems to be justified given the set of sensitivity analyses performed and the use of a randomized design in the effectiveness analysis. The issue of generalisability to other settings or countries was addressed by performing sensitivity analyses. Appropriate comparisons were made with other studies.
Implications of the study The findings suggest that many patients with intra-abdominal infections are candidates for early conversion from IV to oral antibacterial therapy which results in economic savings.
Source of funding Supported in part by an unrestricted grant from Bayer Canada, Inc.
Bibliographic details Walters D J, Solomkin J S, Paladino J A. Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin in the treatment of intra-abdominal infections. PharmacoEconomics 1999; 16(5 Part 2): 551-561 Indexing Status Subject indexing assigned by NLM MeSH Abdomen; Aged; Anti-Infective Agents /economics /therapeutic use; Bacterial Infections /drug therapy /economics; Cilastatin /economics /therapeutic use; Ciprofloxacin /economics /therapeutic use; Cost-Benefit Analysis; Double-Blind Method; Drug Combinations; Female; Humans; Imipenem /economics /therapeutic use; Male; Metronidazole /economics /therapeutic use; Middle Aged; Protease Inhibitors /economics /therapeutic use; Thienamycins /economics /therapeutic use AccessionNumber 21999008333 Date bibliographic record published 31/08/2000 Date abstract record published 31/08/2000 |
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