Background-The adverse eVects of long term treatment of asthma with the short acting agonist fenoterol have been established in both epidemiological and clinical studies. A study was undertaken to investigate the eYcacy and safety of long term treatment with salbutamol and salmeterol in patients with mild to moderate bronchial asthma. Methods-In a two centre double dummy crossover study 165 patients were randomly assigned to receive salbutamol 400 µg qid, salmeterol 50 µg bid, or placebo via a Diskhaler. All patients used salbutamol as required for symptom relief. The study comprised a four week run in and three treatment periods of 24 weeks, each of which was followed by a four week washout. Asthma control was assessed by measuring mean morning and evening peak expiratory flow rate (PEFR), a composite daily asthma score, and minor and major exacerbation rates. Washout assessments included methacholine challenge and bronchodilator dose response tests. Analysis was by intention to treat. Results-Data from 157 patients were analysed. Relative to placebo, the mean morning PEFR increased by 30 l/min (95% CI 26 to 35) for salmeterol but did not change for salbutamol. Evening PEFR increased by 25 l/min (95% CI 21 to 30) and 21 l/min (95% CI 17 to 26), respectively (p<0.001). Salmeterol improved the asthma score compared to placebo (p<0.001), but there was no overall diVerence with salbutamol. Only daytime symptoms were improved with salbutamol. The minor exacerbation rates were 0.29, 0.88, and 0.97 exacerbations/patient/ year for salmeterol, salbutamol and placebo, respectively (p<0.0001 for salmeterol). The corresponding major exacerbation rates were 0.22, 0.51 and 0.40, respectively (p<0.03 for salmeterol). For salbutamol the asthma score deteriorated over time (p<0.01), and the time spent in major exacerbation was significantly longer compared with placebo (12.3 days (95% CI 4.2 to 20.4)) versus 8.4 days (95% CI 5.2 to 11.6), p = 0.02). There was no evidence of rebound deterioration in asthma control, lung function, or bronchial hyperresponsiveness following cessation of either active treatment, and no evidence of tolerance to salbutamol or salmeterol. Conclusions-Regular treatment with salmeterol is eVective in controlling asthma symptoms and reduces minor more than major exacerbation rates. Salbutamol was associated with improved daytime symptoms but subtle deterioration in asthma control occurred over time. Salbutamol should therefore be used only as required. (Thorax 1998;53:744-752)

Background-Studies of mortality from

The initial retrospective surveys performed in New Zealand" in the early 1980s to examine the possible causes of the epidemic of asthma deaths which began to occur in the late 1970s proved useful in generating a number of hypotheses. These included: (1) an increase in the prevalence of asthma,56 (2) an increase in the severity of asthma,7 (3) changes in the provision of, and access to, primary health care,"'0 (4) direct drug toxicity, due either to individual drugs or a combination of drugs,"1 The more recent literature relating to the New Zealand epidemic has included case control studies,'14-8 retrospective dynamic cohort studies,'920 and randomised clinical trials2' and has refocused interest back on inhaled agonists as the potential cause of the epidemic. However, a closer scrutiny of the trends in both asthma mortality and morbidity from the late 1970s through to the early 1990s suggests that there were likely to have been other factors which not only contributed to the epidemic, but also to the subsequent decline in asthma mortality and morbidity. These factors will be reviewed in this paper.

These results suggest that while PEF variability may reflect AHR for the purposes of epidemiologic studies, it is unlikely to be useful as a simple 'non-invasive' means of assessing AHR in individual patients. More complex measures of PEF variability do not have an advantage over simpler measures such as mean morning PEF.

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