j3-Blockers vs Calcium Channel Blockers vs ACE Inhibitors Dahlof C, Dimenas E, Kendall M, Wiklund I. Quality of life in cardiovascular diseases. Emphasis on P-blocker treatment. Circulation 84 (Suppl. VI): 108-118, 1991 Summary

The use of J3-blockers in therapeutics is well established. This article poses 3 questions: (a) what are the particular advantages of J3-blockers, and are these important? (b) what problems are caused by J3-blockers, and how serious are these? (c) is it possible to maximise the benefits and minimise the unwanted effects by choosing a particular J3-blocker or a specific pharmaceutical formulation? The first question is barely addressed but the other two are discussed by reviewing methods for assessing quality of life in the specific field of hypertension, and examining the association between adverse effects of J3-blockers and their physicochemical and pharmacodynamic properties. There is an interesting section contrasting the severity and nature of adverse effects in different populations. The tolerability of J3-blockers demonstrated in large trials after myocardial infarction provides a contrast with the numerous measures of impaired performance detectable in healthy volunteers. There is also a suggestion that J3-blockers are tolerated more readily by patients with type A personalities. The influence of plasma concentration on adverse effects is mentioned briefly, with some support for using a controlled release formulation to reduce fluctuationand adverse effects at peak concentrations. The authors conclude that hydro/lipophilicity is of minor importance, but J31-selectivity may have some impact on quality of life, and J31-selective agents are equivalent to calcium channel blockers and ACE inhibitors but (implicitly) superior to nonselective J3-blockers. Commentary

What relevance does this article have to pharmacoeconomics? There is no direct discussion of costs or of therapeutic benefit. The focus is on adverse effects, and the article concludes that J31-se-

lective J3-blockers are no worse in this respect than calcium channel blockers or ACE inhibitors. The most important impact of J3-blockade on cardiovascular mortality is found in patients following myocardial infarction. Furthermore, it is this group of patients who appear to suffer least from the adverse effects of J3-blockers (and for which the other two classes of agents have uncertain benefits). Treatment of mild to moderate hypertension is the economically problematic area. Few patients derive benefit from treatment (see references below), yet many are aware of medication-induced impairment of quality of life. This review provides support for a level playing field for a marketing battle between J31-selective J3-blockers, calcium channel blockers and ACE inhibitors. Tables are provided which purport to describe the effects of J3-blockers on quality oflife. The first compares the agents with respect to J31/J32 selectivity, hydro/lipophilicity and partial agonist activity. The second and third compare nonselective or J31selective J3-blockers with placebo, ACE inhibitors and calcium channel blockers. However, there are no explicit citations which could support the opinions expressed in the tables, nor are criteria defined for classification of effects on a simple positivenegative scale. Yet it is these tables which are the most strikingly accessible feature of the review and which are the mainstay of the conclusions. I believe that the pharmacoeconomic impact of this article will be to provide marketing support for metoprolol (2 of the 4 authors are affiliated to the original developer of metoprolol). The 3 simple tables will probably appear in glossy multi-colour detail material which could readily be used to demonstrate the superiority of metoprolol over most other J3-blockers, and its equivalence to ACE inhibitors and calcium channel blockers. At this point the pharmacoeconomic advantage of metoprolol becomes clear. If it is accepted that the tolerability profile of metoprolol is no different from those of ACE inhibitors and calcium channel blockers, and its efficacy in lowering blood pressure is equivalent, then the only discriminating factor is cost. In New Zealand, metoprolol is approximately half the cost of either of the other classes of agents and

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Current Comment

therefore would appear to be more cost-effective in treatment of hypertension. Putting economics aside, the review provides a useful description of the influence of {1-blockade on CNS function. These effects are difficult to quantitate, and their mechanisms are not elucidated, but they do provide strong support for a functional role for {1-adrenoceptors beyond the heart, blood vessels and bronchial tree.

References Australian national blood pressure study management team. The Australian therapeutic trial on mild hypertension. Lancet I: 1261-1267, 1980 MRC Working party. MRC trial of treatment of mild hypertension: principal results. British Medical Journal 291: 97-104, 1985

Summary and commentary by Dr N.H.G. Holford, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand

Importance of Side Effects in Treating Impetigo Rice TD, Duggan AK, DeAngelis C. Cost-effectiveness of erythromycin versus mupirocin for the treatment of impetigo in children. Pediatrics 89: 210 - 214, 1992 Summary

The paper by Duryea Rice and others from the Johns Hopkins University Department of Pediatrics reports a cost-effectiveness study on a controlled comparison of 10 days of topical 2% mupirocin versus oral erythromycin for the treatment of impetigo in children. Structured interviews with parents were used to collect the cost and effect data. Clinical and bacteriological effectiveness were very similar for both therapies. The proportion of patients experiencing side effects was 2-fold higher in the erythromycin group, and the proportion of systemic side effects was also significantly greater (p = 0.0003). The mean number of days lost either from school or from work (by the parents) was greater in the erythromycin group (p < 0.04). The mean total cost of therapy was $US5.40 higher for

the mupirocin group (p < 0.05). However, the willingness of the parents to pay more for a medication that would not produce the experienced side effect was significantly greater in the erythromycin group (p < 0.04). The authors conclude that the higher cost of topical mupirocin compared with oral erythromycin is offset by increased (mainly systemic) side effects of erythromycin, leading to more school days and workdays lost with erythromycin. Commentary

The results of the study by Duryea Rice et al. are additional to comparative results reported over the last 4 years by at least 3 other groups (Barton et al. 1989; Goldfarb et al. 1988; McLinn 1988). They all confirm the change which occurred in the microbiological aetiology of impetigo, with a very clear shift toward Staphylococcus aureus, which is the most prevalent aetiological agent nowadays. All 4 studies, comparing topical mupirocin with oral erythromycin (the standard therapy) showed that both treatments were highly and equally efficacious from both the clinical and the bacteriological point of view. All 4 studies agree on the higher rate of side effects observed with oral erythromycin when compared with topical mupirocin (13 vs 0%, 15 vs 0% and 17 vs 8% in the previously cited studies; 43 vs 22% in Duryea Rice's study, with a major emphasis on systemic, mainly gastrointestinal side effects occurring during erythromycin). It is not astonishing that a drug such as mupirocin, which is not absorbed systemically, is practically devoid of systemic side effects, while its local side effects have been attributed to the use of polyethylene glycol as vehicle. Although topical mupirocin is more expensive than oral erythromycin, the detailed analysis in the present study illustrates the need to include parameters other than the cost of drugs in any pharmacoeconomic evaluation. In the present case, the high rate of systemic side effects occurring during oral erythromycin therapy led to a significant willingness of parents to pay for an alternative medication that would not produce the observed side effect. Topical mupirocin is a good alternative, which could become the primary mode of therapy of impetigo in the coming years. None of the cited

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studies examined the risk of emergence of microbial resistance to mupirocin. With a more widespread usage of this topical agent, this question will obviously will need to be addressed.

Correspondence

Goldfarb J, Crenshaw D, O'Horo J, Lemon E, Blumer JL. Randomized clinical trial of topical mupirocin versus oral erythromycin for impetigo. Antimicrobial Agents and Chemother. . apy 32: 1780-1783, 1988 McLinn S. Topical mupirocin vs. systemIc erythromycin treatment for pyoderma. Pediatric Infectious Diseases Journal 7: 785-790, 1988

References Barton LL, Friedman AD, Sharkey AM. Impetigo contagiosa III. Comparative efficacy of oral erythromycin and topical muplrocin. Pediatric Dermatology 6: 134-138, 1989

Should Indirect Costs and Benefits be Included? In his recent article (PharmacoEconomics 1: 312324, 1992) Doctor Nyren has done a superb job in analysing a confusing literature on the economic impact of functional dyspepsia and the probable outcomes of treatment. Like many cost of illness studies the final analysis is dominated by estimates of indirect costs associated with sickness leave due to functional dyspepsia. This remains a controversial area and I think it is appropriate for the Journal to facilitate further debate of the issues. The question really is: are the 'costs' associated with sickness absence in industrial societies really costs, and do treatments that reduce sickness absence result in real savings? I can understand that in developing countries widespread nutritional deficiencies and infestational diseases are likely to lead to reduced productive capacity, which may be improved by effective interventions. I can also understand that in developed countries productive capacity could be affected seriously in the short term by a major influenza epidemic. However, I have trouble believing that in developed countries, with high unemployment, productive capacity will be altered to any significant degree by treatment of the common chronic diseases. Most manufacturing companies have spare capacity that can cope with

Summary and commentary by Dr J. Boeiaert, Unit for Renal and Infectious Diseases, Algemeen Ziekenhuis, St Jan, B-IOO Bruges, Belgium.

sickness absence, and workers who have to leave their jobs through illness can be replaced from the large pool of unemployed. The costs associated with these manoeuvres are really transfer costs and are difficult to incorporate in economic analysis. I think that in conducting pharmacoeconomic analyses, investigators have to justify the inclusion of indirect cost and benefits and their valuation of them. To value these at full wage rates is unrealistic. Equally, it is probably wrong to ignore them completely. . The Australian guidelines for economic analysis of pharmaceuticals put the onus on the applicant to justify the inclusion of indirect costs and benefits, and advise that the analysis should be performed with and without them to determine their effect on the overall conclusions. However, I accept that this is a truly controversial area and I believe that PharmacoEconomics can contribute to our knowledge by encouraging a debate in this area. David A. Henry Senior Lecturer in Clinical Pharmacology University of Newcastle Newcastle, Australia Nyren 0, Lindberg G, Lindstrom G, Marke L-A, Seensalu R. Economic costs of functional dyspepsia. PharmacoEconomics 1: 312-324, 1992