|Macrolides in community-acquired pneumonia and otitis media
|Canadian Coordinating Office for Health Technology Assessment
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 three macrolides; erythromycin compared toazithromycin or clarithromycin for the treatment of community acquired pneumonia (CAP) and otitis media.
Economic study type
Patients who had received a macrolide, specifically erythromycin, azithromycin or clarithromycin for the treatment of CAP and otitis media.
Primary care. The economic study was conducted by the Canadian Co-ordinating Office of Health Technology Assessment, Ottawa, Ontario, Canada.
Dates to which data relate
Effectiveness and resource data were collected for the period 1 April to 30 September 1993 and from a search of published literature starting in 1985. The price dates were not stated.
Source of effectiveness data
Effectiveness data were derived from a review of published literature.
A decision analysis model was used to combine probabilities of health outcomes and costs.
Outcomes assessed in the review
The outcomes assessed were clinical efficacy failure rates and discontinuation rates resulting from adverse effects when using macrolides for treating otitis media and CAP.
Study designs and other criteria for inclusion in the review
Study designs identified included prospective randomised studies which compared one macrolide to another macrolide or to another antibiotic in non-hospitalised patients. Non English language studies were excluded.
Sources searched to identify primary studies
Criteria used to ensure the validity of primary studies
Methods used to judge relevance and validity, and for extracting data
Number of primary studies included
Thirteen studies were included in the analysis.
Methods of combining primary studies
Clinical efficacy failure rates and discontinuation rates were estimated by weighting the rates in each study by the number of patients included in the efficacy or safety analysis respectively. A 'true' meta-analysis was not conducted, and no formal hypothesis testing was done to determine statistical significance.
Investigation of differences between primary studies
Results of the review
Very few head-to-head trials comparing azithromycin and clarithromycin were available for either condition. Point estimates for azithromycin in pneumonia and erythromycin in otitis were based on only four studies (44 patients) and two studies (133 patients) respectively. The weighted averages from the clinical trials were as follows:
CAP: Discontinuation due to side effects:
10.4% (95% CI: 8.5% - 12.7%) for erythromycin,
3.7% (95% CI: 2.2% - 5.8%) for clarithromycin
and 1.2% (95% CI: 0.3% - 3.1%) for azithromycin.
Clinical efficacy failure:
5.1% (3.3% - 7.5%) for erythromycin,
2.9% (1.4% - 5.4%) for clarithromycin and
and 4.9% (0.5% - 17.6%) for azithromycin.
Otitis media:Discontinuation due to side effects:
2.1% (0.4% - 6.2%) for erythromycin sulfisoxazole,
1.9% (1.0% - 2.6%) for clarithromycin
0.3% (0.1% - 0.7%) for azithromycin.
Clinical efficacy failure (Otitis Media):
6.0% (2.6% - 11.9%)for erythromycin
7.9% (6.1% - 10.2%) for clarithromycin
and 6.6% (5.3% - 8.2%) for azithromycin.
Success and failure rates were then calculated using the decision analysis model. Four outcomes were evaluated, two successful, one with and one without a follow up physician visit (groups 1 and 2) and failure due to poor clinical efficacy (group 3) or discontinuation due to adverse effects(group 4). These success and failure rates were 85% and 15% respectively when using erythromycin for CAP and 92% and 8% when using this macrolide for otitis media. Similarly the success and failure rates for clarithromycin were 93% and 7% for CAP and 91% and 9% for Otitis media. For azithromycin the rates were 94% and 6% for CAP and 93% and 7% for otitis media. The authors concluded that although there were differences in efficacy between the drugs for the treatment of pneumonia, the effectiveness of the three drugs in treating otitis media was the same.
Measure of benefits used in the economic analysis
For CAP, additional treatment success gained was used to estimate the measure of benefit. Since the clinical analysis demonstrated that there were no differences in the clinical benefits between the three drugs in treating otitis media, that part of the economic analysis was based on the difference in costs only.
The costs were calculated from the perspective of the Ministry of Health, including the costs of medication and physician visits, but not hospitalisation costs. The costs of prescriptions and follow up visits over a 28 day period were estimated. For CAP, the average total cost per erythromycin prescription was obtained from the Saskatchewan database. Drug costs for azithromycin and clarithromycin were obtained from the manufacturers. For otitis media all drug costs were obtained from the manufacturers. To calculate initial prescription costs a 10% wholesale mark-up, pharmacist dispensing fee and a 35% patient co-payment were included. Follow-up prescription costs were obtained from the Saskatchewan database. The costs of physician visits were obtained from the Saskatchewan Health Payment Schedule for Physician Services and, where more than one follow up visit was required, the weighted average cost was calculated. Annual costs were estimated for each Canadian province by use of a provincial population weight and an estimate of the number of patients requiring treatment, identified through retrospective access to the Saskatchewan database and weighted prescription costs. No discounting was used in the study.
Sensitivity analysis was performed on the following parameters: results of clinical analysis, ranges of discontinuation rates due to side effects and clinical efficacy failure rates, distribution of patients in success outcome groups, province specific resource costs, drug prices, the elimination of patient co-payments, and comparison of amoxicillin-clavulanate to azithromycin or clarithromycin in otitis media. The methods used for sensitivity analysis were not stated although some use was made of threshold analysis for two of the parameters.
Estimated benefits used in the economic analysis
The estimated benefits used were an increase in the success rate of 8% for clarithromycin versus erythromycin, and9% for azithromycin versus erythromycin in the treatment of CAP.
The expected costs per patient per episode for the three drugs were:
For CAP:$67 for erythromycin, $78 for clarithromycin, and $78 for azithromycin.
For otitis media:$78 for erythromycin, $79 for clarithromycin, and $77 for azithromycin.
For CAP, the incremental costs of clarithromycin and azithromycin compared to erythromycin were both $11.
Synthesis of costs and benefits
The incremental costs per additional successfully treated patient for CAP were $131 for clarithromycin and $123 for azithromycin, compared to erythromycin. Both costs and benefits of the three therapies for otitis media were similar and no analysis was reported. The model was robust to sensitivity analysisand, even if success rates for the new drugs were 100%, they would still remain more costly than erythromycin for the treatment of CAP. The additional costs of using either azithromycin or clarithromycin for each province for the treatment of CAP were also reported. In Saskatchewan the total treatment cost per year was $52,000 using erythromycin and there would be $15,000 in additional costs if the newer macrolides were used. Similarly the total costs and additional costs for the other provinces were estimated to be $166,000 and $74,000 for British Columbia, Alberta $147,000 and $38,000, Manitoba $36,000 and $16,000, Ontario $433,000 and $247,000, Quebec $319,000 and $96,000, New Brunswick $23,000 and $16,000, Nova Scotia $36,000 and $11,000, Prince Edward Island $4000 and $2000 and Newfoundland $18,000 and $10,000 for total erythromycin costs and additional costs from the newer macrolides.
The same estimations were also made for the treatment of otitis media, which indicated that there may be a reduction in total costs by the use of azithromycin, although this resulted from very small and insignificant differences in the total expected cost of each drug (i.e. $1). These results should be treated with some caution, and are not presented here.
For community acquired pneumonia, azithromycin and clarithromycin were more effective than erythromycin, however the additional cost of achieving an additional treatment success with these drugs was $123-131, and erythromycin therefore remains the least expensive option. There were no differences in costs or effectiveness between the three treatments with regard to otitis media and a cost-effectiveness analysis was not performed.
CRD COMMENTARY - Selection of comparators
A justification was given for the comparators used. The comparators azithromycin and clarithromycin are new generation macrolides which have improved pharmacokinetic properties and reduced adverse effects compared with erythromycin which is commonly used for the treatment of CAP and otitis media.
Validity of estimate of measure of benefit
The estimate of benefit is based on the results of a literature review which may be biased as the methods used to identify literature have not been adequately described, non-English language articles were excluded, and no study details were provided. The authors also noted that the model did not use formal methods of meta-analysis to weight studies, did not explicitly take into account issues of compliance, and very few studies were found comparing azithromycin and clarithromycin directly for both conditions. Very limited details of the methodology used to gain estimates of effectiveness were provided.
Validity of estimate of costs
Although information was provided on costs and the source of costs the price year used was not reported. Costs were reported to be from the perspective of the health care payer, although patient co-payments were included in costs. The costs of hospitalisation, management of side effects and drug interactions, and diagnostic and laboratory procedures were not included in the analysis which might affect cost-effectiveness.
The study may not be generaliseable to other provinces in Canada or elsewhere. Prices in Saskatchewan have been used and in particular the incidence of the use of erythromycin in Saskatchewan may not be appropriate for other areas if there is any great variation in clinical practice in this province. In addition the prevalence rates for respiratory infections were estimated from a patient database from April to September and may not be accurate or generaliseable across an entire year.
Implications of the study
Well designed primary studies comparing all aspects of clinical effectiveness and economic outcomes for macrolides in a number of settings should be conducted. In addition it may also be useful to conduct a well designed systematic review/meta analysis of relevant publications, including those not in the English language.
Canadian Coordinating Office for Health Technology Assessment. Macrolides in community-acquired pneumonia and otitis media. Ottawa, ON, Canada: Canadian Coordinating Office for Health Technology Assessment. Technology Overview: Pharmaceuticals, 8. 1997
Other publications of related interest
Tasch R F, Kunz K C, Marentette M A, Reldeimer D A. A therapeutic and economic evaluation of macrolide antibiotics. Ottawa: Canadian Co-ordinating Office for Health Technology Assessment (CCOHTA), 1997.
Subject indexing assigned by CRD
Anti-Bacterial Agents /therapeutic use; Azithromycin /therapeutic use /economics; Clarithromycin /therapeutic use /economics; Community-Acquired Infections /drug therapy; Costs and Cost Analysis; Erythromycin /therapeutic use /economics; Otitis Media /drug therapy; Pneumonia /drug therapy
Date bibliographic record published
Date abstract record published