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A 1-year community-based health economic study of ciprofloxacin vs usual antibiotic treatment in acute exacerbations of chronic bronchitis: the Canadian Ciprofloxacin Health Economic Study Group |
Grossman R, Mukherjee J, Vaughan D, Eastwood C, Cook R, LaForge J, Lampron N |
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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 use of the antibiotic, ciprofloxacin, in the treatment of acute exacerbation of chronic bronchitis (AECB). The dose recommended was 500-mg bid, but dose and duration were left to the physician's discretion as was the decision to prescribe ciprofloxacin for subsequent AECBs within the follow-up period in the event of treatment failure.
Economic study type Cost-effectiveness analysis and cost-utility analysis.
Study population Adult outpatient men and women aged 18 and over, presenting with an attack of AECB (including 2 or more of, increased dyspnea, increased sputum volume or sputum purulence), with chronic bronchitis who had suffered 3 or more exacerbations of bronchitis in the past year and who were capable of completing questionnaires and a diary. The following were excluded from the study population: patients with a history of allergy to carboxyquinolone derivatives, patients who were (or could possibly be) pregnant, nursing mothers, those with severe respiratory tract infection requiring parenteral antimicrobial therapy or mechanical ventilatorysupport, significant renal impairment, a diagnosis of lung or chest cavity malignancy, cancer, cystic fibrosis, tuberculosis or psychiatric disorders and known HIV-positive individuals.
Setting Primary care (outpatient general practice, Canada). The economic study was carried out in Canada.
Dates to which data relate Patients were enrolled in the study between November 1993 and June 1994 and followed up for 12 months. Cost data were collected at the same time but the price year was not stated.
Source of effectiveness data Evidence for final outcomes was based on a single study.
Link between effectiveness and cost data Costing was undertaken prospectively on the same patient sample as that used in the effectiveness study.
Study sample Power calculations were used to determine sample size. A sample size of 99 in each group was initially considered large enough as this would have been able to detect a difference of 8.5 infection days per year, with a two-tailed alpha of 0.05 and 80% power, assuming a baseline rate of infection of 32.4 (+/- 21) infection days per year. Since this difference was not found, an attempt was made to recruit a larger sample (of 300) by extending the enrolment period by 2 months from 6 to 8 months, but accrual was stopped at 240. A total of 240 patients were enrolled in the study and randomised into the treatment and control groups, 120 in each group. The authors considered the study to be underpowered and stated that a clinically relevant difference "is a matter of considerable debate". The percentage of patients invited to participate who refused was not given. After randomisation 5 (4%) in the ciprofloxacin group and 13 (11%) in the usual care group were excluded.
Study design The study was a randomised controlled trial, multi-centred at approximately 50 centres (exact number was not given). The study was not blinded but an independent academic committee made decisions on patient evaluability, whether or not hospitalisations were respiratory related and on analysis plans. These decisions were done in a blinded fashion using dummy patient identification numbers. Follow-up continued for 12 months from the initial treatment with set follow-up visits at 3, 6, 9 and 12 months. Patients were also asked to return for an initial follow-up visit within a week of disappearance of symptoms (self-defined). Loss to follow-up was 5 (4%) in the ciprofloxacin group, 3 because of no follow-up after the first AECB and 2 because of the diagnosis of cancer. In the usual care group loss to follow-up was 13 (11%), 11 because of no follow-up after the first AECB and 2 because of cancer. Loss to follow-up later in the study period was not mentioned.
Analysis of effectiveness 120 were randomised in each group but 18 patients were lost to follow-up as described above. The authors called the remainder "the intent to treat population" and these (115 in the ciprofloxacin and 107 in the usual care group) were analysed on an intention to treat basis. However the complete sample was not analysed and the study was therefore not truly based on intention to treat. Primary health outcomes were quality-adjusted life years (QALYs) gained and symptom days averted. A quality of life year for each patient was based on 3 self-administered questionnaires, the Nottingham Health Profile, the St. George's Respiratory Questionnaire (a disease specific measure) and the Health Utilities Index. Symptom days were defined by the patient. Further analysis was conducted on sub-groups of the sample according to the number of 5 risk factors affecting each patient: moderate or severe bronchitis, 4 or more AECBs in the past 12 months, chronic bronchitis of more than 10 years' duration, age over 56 years and 3 or more abnormal markers of comorbidity.
Effectiveness results The total number of AECB symptom days per patient in the ciprofloxacin group was 42.9 (+/- 2.8), (SE) and in the usual care group it was 45.6 (+/- 3.0) (SE). The treatment difference of 2.8 (+/- 4.1) was not statistically significant (p=0.50; 95% CI: -5.3 to 10.8)The mean QALY per patient receiving ciprofloxacin was 0.791 (+/- 0.016), and 0.760 (+/- 0.018) per patient receiving usual care. The difference of 0.031 (+/- 0.023) was not statistically significant (95% CI: -0.015 to 0.077). If a patient had all 5 risk factors the use of ciprofloxacin led to 11.5 (+/- 10.0) fewer AECB days and 0.13 QALYS gained.
Clinical conclusions "There was a slight but not statistically significant improvement in all quality of life measures with ciprofloxacin over usual care." "Treatment with ciprofloxacin tended to accelerate the resolution of all AECBs compared to usual care."
Measure of benefits used in the economic analysis QALYs used in the economic analysis were derived from the Health Utilities Index completed by patients at regular and follow-up visits based on a standard area under the curve approach. Symptom days were defined by patients and reported by questionnaire, (it was stated in the criteria for entry to the study that patients must keep a diary). Symptom days averted were the difference between strategies.
Direct costs Costs were given from a societal viewpoint. Patients were charged the usual amount for health care. Ciprofloxacin was given free though included in the costing. Quantities and prices were not given. All costs were given as the mean, plus or minus the standard deviation. No price year was given. Costs were given for antibiotics for AECBs, concomitant medications, outpatient resources and hospitalisations. Total costs per patient including indirect costs were given.
Statistical analysis of costs Mean costs plus or minus standard deviation were used.
Indirect Costs The indirect costs given were: time lost from work and out of pocket expenses for patients and caregivers. These were measured using patients' self-assessments. They were presented as the mean per patient plus or minus the standard deviation. It was not stated whether hours lost from work were multiplied by a constant factor or whether patients' individual earnings determined the amount used.
Estimated benefits used in the economic analysis The total number of AECB symptom days per patient in the ciprofloxacin group was 42.9 (+/- 2.8), (SE) and in the usual care group it was 45.6 (+/- 3.0) (SE). The treatment difference of 2.8 (+/- 4.1) was not statistically significant (p=0.50; 95% CI: -5.3 to 10.8)The mean QALY per patient receiving ciprofloxacin was 0.791 (+/- 0.016), and 0.760 (+/- 0.018) per patient receiving usual care. The difference of 0.031 (+/- 0.023) was not statistically significant (95% CI: -0.015 to 0.077). If a patient had all 5 risk factors the use of ciprofloxacin led to 11.5 (+/- 10.0) fewer AECB days and 0.13 QALYS gained.
Cost results The total cost of the ciprofloxacin group was Can$3,194 (+/-Can$6,575) and the cost of the usual care group was Can$2,617 (+/-Can$3,300). Time lost from work totalled Can$291 (+/- Can$1161) for the ciprofloxacin group and Can$628 (+/- Can$1,716) for the usual care group. Out of pocket expenses totalled Can$100 (+/- Can$136) for the ciprofloxacin group and Can$150 (+/- Can$278) for the usual care group. The incremental cost difference in favour of usual care was Can$578 (95% CI: -Can$778 to Can$1,932) This was not statistically significant.
Synthesis of costs and benefits The additional cost associated with ciprofloxacin treatment was Can$209 (Can$578/2.8 days) per symptom day averted. The cost per QALY gained for ciprofloxacin was Can$18,588 (Can$578/0.031).
Authors' conclusions Although results were not statistically significant, treatment with ciprofloxacin tended to accelerate the resolution of all AECBs. Trends in all clinical outcomes and quality of life measurements favoured ciprofloxacin. In the case of patients suffering moderate to severe bronchitis and at least 4 AECBs in the previous year ciprofloxacin offered substantial clinical and economic benefits.
CRD COMMENTARY - Selection of comparators The reason for the selection of comparator was clear.
Validity of estimate of measure of benefit None of the results were statistically significant. It is therefore not justified to proceed to the synthesis of costs and benefits.
Validity of estimate of costs Insufficient details were given, in particular of the measurement of indirect costs. No quantities or prices were given so that generalisation is difficult. None of the cost differences were significant. No details were given of how costs were reworked for the analysis of subgroups.
Other issues The authors stated "The size of the difference that can be considered clinically relevant is a matter of considerable debate", however they had designed the study to detect a difference of 8.5 infection days. They expected the use of first line antibiotics or none and found general practitioners' use of second line antibiotics in the comparator group surprising. When this resulted in a non-significant difference they first increased the sample size and secondly claimed "trends" in benefits that are invalid. They also presented the results of the sub-samples selectively to favour the intervention. The conclusions, therefore, should be treated with caution.
Source of funding Supported by Bayer Canada, Inc
Bibliographic details Grossman R, Mukherjee J, Vaughan D, Eastwood C, Cook R, LaForge J, Lampron N. A 1-year community-based health economic study of ciprofloxacin vs usual antibiotic treatment in acute exacerbations of chronic bronchitis: the Canadian Ciprofloxacin Health Economic Study Group. Chest 1998; 113(1): 131-141 Indexing Status Subject indexing assigned by NLM MeSH Adolescent; Adult; Anti-Infective Agents /adverse effects /economics /therapeutic use; Bronchitis /drug therapy /economics; Canada; Chronic Disease; Ciprofloxacin /adverse effects /economics /therapeutic use; Cost-Benefit Analysis; Female; Follow-Up Studies; Health Care Costs; Hospitalization /economics; Humans; Male; Middle Aged; Predictive Value of Tests; Quality-Adjusted Life Years; Recurrence; Treatment Outcome AccessionNumber 21998000177 Date bibliographic record published 30/06/1999 Date abstract record published 30/06/1999 |
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