Saturday 13 September 1975
INHALED CORTICOSTEROIDS COMPARED WITH ORAL PREDNISONE IN PATIENTS STARTING LONG-TERM CORTICOSTEROID THERAPY FOR ASTHMA
systemic corticosteroids will usually supplement to inhaled therapy.
A CONTROLLED TRIAL BY THE BRITISH THORACIC AND
sone valerate aerosols became ment of asthma it seemed
Inhaled beclomethasone dipropionate and inhaled betamethasone valerate have been compared with oral prednisone in the treatment of 75 patients with asthma who were starting long-term corticosteroids for the first time. Both of the inhaled corticosteroids controlled asthma as well as did oral prednisone in those who had responded to therapy in the initial period of the trial. A daily dose of 400 µg of inhaled drug was approximately equivalent to 7·5 mg daily of prednisone. Prednisone suppressed the adrenal response to tetracosactrin, whereas the mean responses in the groups receiving inhaled corticosteroids did not change significantly from pre-trial values. The 30% incidence of other systemic unwanted effects of prednisone contrasted sharply with the low incidence (5%) of symptomatic oropharyngeal candidiasis in the patients receiving inhaled corticosteroids. In a sample of 19 patients no change in exfoliative cytology was detected over the period of the trial nor was there any evidence of fungal colonisation of the bronchial tree. There was no difference between the three treatment groups in the number of antibiotic courses prescribed. The persistent production of sputum made no difference to the response to inhaled corticosteroids. Patients not on sodium cromoglycate did as well in the trial as those receiving sodium cromoglycate. Both inhaled beclomethasone dipropionate and inhaled betamethasone valerate have advantages over oral prednisone in the maintenance treatment of patients with asthma, but in the management of exacerbations
The trial was designed and coordinated by the B.T.T.A. research fellow, Dr I. A. Campbell, on behalf of the clinical trials subcommittee of the B.T.T.A. whose members were Dr A. R. Somner (chairman), Dr J. H. Angel, Dr K. M. Citron, Dr T. J. H. Clark, Prof. J. W Crofton, Prof. P. C. Elmes, Dr J. A. R. Friend, Dr R. M. Greenwood, Dr Elizabeth Hills, Dr J. W. Paterson, Dr A. Pines, Dr H. C. Smyllie, and Dr J. E. Stark. The report was prepared by 7933
WHEN beclomethasone TUBERCULOSIS
dipropionate and betamethaavailable for the
establish their place in the therapy of patients already maintained on systemic corticosteroids,l but also to investigate their efficacy in those judged to require long-term corticosteroids for the first time. Consequently the British Thoracic and Tuberculosis Association (B.T.T.A.) initiated a multi-centre study comparing one inhaled corticosteroid with another, and with prednisone., in patients with asthma not previously receiving long-term corticosteroids. The primary aims of the study were to compare both the control of asthma achieved with these three treatments and the unwanted effects. A secondary aim was to find the doses required to attain satisfactory control of asthma. Patients Patients with asthma, aged 16 years or more, who were of using a pressurised inhaler and who were being considered by their physician for long-term corticosteroid therapy, were accepted for the study, provided they had not received more than 3 months’ corticosteroids during the previous 12 months and none in the previous month. Patients in status asthmaticus, pregnant patients, and patients with malignant disease or tuberculosis were not taken into the study.
Design and Dosages The study
was of a multi-centre, double blind, nondesign. Patients were stratified according to whether or not they were receiving sodium cromoglycate, crossover
and within each stratum there was a random allocation in balanced blocks of 3 to one of three treatment groups:
(1) Prednisone tablets + placebo aerosol (P). (2) Placebo tablets +beclomethasone dipropionate aerosol
(BDP). (3) Placebo tablets+ betamethasone
Thus all patients received both an active drug and a placebo. Prednisone was formulated as a 5 mg tablet. The BDP and BV aerosols delivered 100 g of beclomethasone dipropionate or betamethasone valerate per puff. The placebo preparations were indistinguishable from the active.
470 In addition, every 4 hours if
patients also used a salbutamol inhaler required. The study was divided into 2 phases:
Phase 1 : during this phase reversibility of airways obstruction assessed, and patients demonstrating 20% or more improvement on their trial regimen were then stabilised on an appropriate maintenance dose. Phase 2: during this phase, which followed immediately on phase 1, the control of asthma and the incidence of unwanted effects were assessed. was
Uniformity of procedure was ensured by meetings of the participating physicians. A short tetracosactrin test2 was performed on entry to the trial. Phase 1. In the first 3 days of this phase each patient recorded peak flow twice daily, at consistent times each morning and evening. The best of three attempts was recorded each time. On the 4th day, treatment was started in a dosage of 4 tablets + 4 double-puffs * of aerosol per day. The patient continued to record peak flow at the same time every morning and evening, and on a diary card noted the dose of tablets + aerosol taken each day, as well as the frequency of use of the salbutamol inhaler. Other bronchodilator tablets, suppositories, or inhalers were tailed off from the 4th day and finally discontinued by the 7th day. Patients normally maintained on sodium cromoglycate continued its regular use. The mean peak flow of the first 3 days of the lst week (i.e., before treatment) was compared with the mean of the peak flow over the last 3 days of the 2nd week in the trial (i.e., after 9-11 days of therapy). Patients achieving a 20% increase in peak flow then began a weekly dose reduction in steps of 1 tablet+1 double-puff of aerosol. All patients were given the freedom to increase their tablets + aerosol to the original maximum of 4 tablets+4 double-puffs on any day that they felt their asthma was not adequately controlled. Dose reduction continued at weekly intervals until
(a) the mean of the peak flow recordings on the last 3 days of the week in question fell unacceptably (e.g., by > 20%) from the mean level achieved on the last 3 days of the 2nd week; or (b) the self-prescribed extra tablets and aerosol had been taken on more than 2 days of the week; or (c) more than 28 double-puffs of salbutamol were used in the week. At this point the daily therapy was increased by one step 1 tablet +double-puff). If, at the end of the following week, the peak flow had risen by an acceptable degree, and self-prescribed extra tablets +aerosol had been taken on no more than 2 days in that week, and double-puffs of salbutamol had amounted to 28 or less in that week, the patient was judged to have reached a stable dose and passed into phase 2 on this dose. Patients reaching a dose of 1 tablet+1 double-puff without having experienced a " failure week " went into phase 2 at this stable dose of
1+1. Phase 2. This lasted 24 weeks, patients being seen every They completed a diary card each day recording:
Number of tablets + double-puffs of aerosol taken. Number of double-puffs of salbutamol taken. (3) A grading of the severity of asthma on a 5 cm line-diagram. (4) Additional courses of corticosteroids prescribed by their
physician or general practitioner. (5) Antibiotic courses. Patients
increase their dose of
tablets + aerosol above stable dose to a maximum of 4 tablets +4 double-puffs per day for 48 hours if their asthma · Double-puff=two discharges from the aerosol, taken two separate but closely successive inspirations.
deteriorated. If this maximum dose did not produce relief they sought medical advice urgently. If a physician had prescribed a course of corticosteroids " failure days " in the or if there had been more than 6 " 4 weeks period (a failure day " was defined as a day on which more than 4 double-puffs of salbutamol were taken or a day on which the patient increased the dose of the tablets + aerosol), the tablets + aerosol were increased by one step for the next 4-week period, this increased dose being the patient’s new stable dose. Peak flow was recorded in the clinic every 4 weeks. The short tetracosactrin test2 was repeated at the end of phase 2. Unwanted effects of therapy were reported by the physician. Direct questions about side-effects were not asked and the oropharynx was examined only if symptoms were spontaneously volunteered by the patient. In addition, at six centres, sputum was examined at regular intervals during phases 1 and 2 for exfoliative cytological change and for fungi. Sputum was collected into 50% alcohol and the specimens were processed either as squash preparations on four separate slides or blocked and examined as histological sections. They were examined microscopically for the presence of fungus, eosinophils, Charcot-Leyden crystals, Curschmann spirals, mucus plugs, and for any changes in quantity or appearance of the bronchial epithelial cells. Patients who, at the end of week 2 of phase 1, had not increased their mean peak flow by 20% or more were withdrawn from the main trial and the majority of these were then given 40 mg of prednisone daily for a week, continuing to record twice daily peak flows. The purpose of this was to obtain evidence of steroid responsiveness or non-responsiveness in these patients.
period of 15 months 166 patients (55 BDP, BV, 57 P) entered the trial from 22 centres. 26 patients (10 BDP, 7 BV, 9 P) were withdrawn from the trial for reasons unconnected with the protocol or In
patients (26 BDP, 24 BV, 15 P) failed to increase their peak flow by 20% at the end of week 2 and were rejected from the main trial at that stage. 46 (17 BDP, 19 BV, 10 P) of these patients were subsequently given 40 mg of prednisone daily for a week: 29 patients again did not respond; but 6 BDP, 8 BV, and 3 P patients increased their peak flow by 20% or more. The 75 patients who increased their peak flow by 20% or more at the end of week 2 are described in table i in terms of sex, sputum production, sodiumcromoglycate status, and mean peak flow before treatment. The mean pre-trial peak flow was greater 65
TABLE I-PATIENTS AVAILABLE FOR MAIN ANALYSIS
471 in the BV group than in the BDP and P groups (P<0-05 by one-way analysis of variance). Patients on sodium cromoglycate behaved in a similar manner to those not on sodium cromoglycate and the subgroups have therefore been combined for the analysis
point applies to the sputum producer/non-sputum producer subgroups which have also been combined for the final analysis. 6 patients in group P were withdrawn from the trial during phase 2 because of systemic side-effects of prednisone. Two BV patients were withdrawn in
TABLE II-CONTROL OF ASTHMA IN PHASE
2-1 because of poor control of asthma and 1 because of increased weight and oedema.
TABLE III-DOSES IN PATIENTS COMPLETING THE TRIAL I
of Asthma and Doses Required
Table 11 summarises the criteria used to assess control of asthma. Over the 24 weeks of phase 2 between 4% and 10% of patients were prescribed courses of prednisone in addition to the trial drugs, there being no significant difference between treatment groups. In terms of increases in the stable dose, the treatment groups again did not differ significantly
from one another. On average, there was less than one " failure day" per month per patient in each group. The mean scores on the line diagrams over the last 4 weeks of phase 2 were similar, and the mean monthly peak flow during phase 2 was much the same in each group. The mean number of antibiotic courses per patient in each group was less than one, there being no difference between BDP, BV, and P in this respect. Thus the patients receiving inhaled corticosteroids were controlled as well as patients on oral prednisone. The mean doses of each treatment at the end of phase 1 and at the end of phase 2 are shown in table In each group the mean stable dose at the end III. of phase 2 was only slightly higher than at the end of phase 1. On average, 400 tig of inhaled corticosteroid provided control of asthma similar to that provided by between 7 and 8 mg of prednisone.
Adrenal Function Short tetracosactrin tests2 were performed both before and at the end of the trial in 19 BDP, 19 BV, and 25 P patients. On entry to the trial there was no significant difference between the groups in pre and post tetracosactrin levels of plasma cortisol (table iv). At the end of the trial the mean pre and post tetracosactrin levels in group P were halved, and were significantly different from the mean levels in the other two groups (P<0-025 by one-way analysis of
TABLE IV-ADRENAL FUNCTION: PLASMA CORTISOL
PRE AND POST TETRACOSACTRIN
values in the BDP and BV
only minimal changes: the differences
statistically significant either within each between the two groups. At the end of the trial, in the BDP and BV groups, a dose-response relationship was observed between the rise in plasmacortisol after tetracosactrin and the dose of inhaled corticosteroid taken during the last month of the trial: for every 200 (Lg increase in daily dose the mean cortisol rise was reduced by 2 g/100 ml.
Effects in Patients Completing Trial None of the BDP and BV patients who completed the trial developed systemic side-effects of corticosteroids. 15% of the P patients completing the trial either developed oedema, dyspepsia, or cushingoid appearance or put on excessive weight. 2 patients (1 P, 1 BV) developed hoarse voice. Only 2 patients developed symptomatic oropharyngeal candidiasis: the fact that they were both in the BV group was not statistically significant. Exfoliative cytological examinations were performed in 19 patients (8 BDP, 6 BV, 5 P) and showed no fungus infection of the sputum The other nor any meaningful cytological changes. microscopic features of the sputum varied from time to
time and showed
correlation with the type
length of time of treatment. Discussion Uncontrolled studies 3-5 have suggested that beclomethasone dipropionate and betamethasone valerate can produce improvement in the symptoms and in the ventilatory function of adult patients with asthma who were not taking long-term systemic corticosteroids when inhaled treatment was started. Short placebocontrolled studies 6-8 have established the superiority of beclomethasone dipropionate and betamethasone valerate over placebo in the control of asthma in adults not receiving long-term corticosteroids. The findings in children 9,10 have been similar. In this study we have compared the two inhaled corticosteroids with oral prednisone in the management of adult patients with asthma who were thought by their physician to need long-term corticosteroid therapy, and who normally would have been given prednisone or other systemic corticosteroid. The existence of airways obstruction reversible by corticosteroid was proven in the 75 patients who entered phase 2 of the trial.
By the subjective and objective criteria used in the of the control of asthma both BDP and BV did as well as the standard drug, prednisone. Using the mean stable dose at the end of phase 1 as an index of the dose at which both the patient and the physician were satisfied initially, and the mean stable dose at the end of phase 2 as an index of the same satisfaction with control of asthma 24 weeks later, we have obtained an approximate idea of dose equivalents: 400 (Lg of inhaled corticosteroid would appear to be equivalent to 7-5 mg of oral prednisone when used to treat asthma in the type of patient studied in this trial. assessment
The observed effect of the dose of inhaled corticosteroid on the adrenal response to tetracosactrin is
interesting, for, although no significant difference emerged between the BDP and BV groups in the mean responses to tetracosactrin at the end of the trial, some individuals gave results which
not " normal ".
(" Normal" =resting plasma-cortisol level of 5 )ig/ 100 ml or more, rising by at least 7 tg/100 ml to a peak of 18 .g/100 ml or more.) Some of these patients had been " abnormal " on entry to the trial, perhaps as a result of pre-trial corticosteroid therapy. Others had been " normal " on entry: in these patients it is possible that the tests were not performed correctly, but it is also possible that inhaled corticosteroid was being absorbed in sufficient quantity to render the response to tetracosactrin
known whether these patients were over-using their corticosteroid inhalers or not. None of them had been prescribed a course of prednisone during the trial, but the possibility that prednisone was being taken unknown to the physician cannot be excluded. 18% of patients in group P were withdrawn from the trial because of systemic unwanted effects of prednisone. Another 15% experienced systemic sideeffects which were not severe enough to warrant withdrawal from the trial. In contrast, 1 patient (2%) on inhaled corticosteroid was withdrawn from the trial because of increase in weight and cedema-changes which the physician felt might have been due to the systemic effect of inhaled betamethasone valerate. Hoarse voice was found in the same proportion of patients in the inhaled corticosteroid groups as in the prednisone group: it may be that the propellants produce this effect or just that it is characteristic of the occasional patient with asthma to develop hoarse voice. Symptomatic oropharyngeal candidiasis was found in 2 patients in the BV group but in none of the BDP or P patients: only further experience can determine whether this difference arose simply by chance. The cytological studies showed no morphological alterations in cells shed from the bronchial epithelium nor was there any evidence of fungal colonisation of the bronchial tree. However, it must be remembered that these observations were made over only a relatively short period of exposure to inhaled corticosteroids. It has been suggested that patients with asthma who produce sputum might not respond as well to inhaled corticosteroids as patients who are not sputumproducers.7 Our results do not support this suggestion, as sputum-producers did as well as patients who did not persistently produce sputum. There was no evidence in this trial to indicate that inhaled corticosteroids might predispose patients to respiratory infections any more than might oral prednisone. Judged by the number of antibiotic courses, the incidence of such infection was equally low in each group.
The proportion of patients entered into the trial whose airways obstruction was not reversed by more than 20% in response to 40 mg prednisone daily was approximately 20%. This failure-rate in patients selected as suitable for long-term corticosteroid therapy was high, even allowing for the fact that keenness to submit patients to the trial might have led to a few unsuitable patients being entered. It
473 that patients should be given a proper trial of corticosteroids before a decision is
made to commit them permanently to such therapy. It would appear from our results that approximately 10% of patients with potentially reversible airways obstruction will need longer than 11 days on 20 mg daily of prednisone to improve by 20% or more. If inhaled corticosteroids are used to assess reversibility, then 30% of patients with such potential reversibility to prednisone will not have achieved this after 11 days. Tests of reversibility in response to corticosteroids should therefore be performed with oral prednisone rather than with inhaled corticosteroids, and should not be regarded as negative until at least 18 days’ therapy has been given. In the population studied in this trial, inhaled beclomethasone dipropionate or betamethasone valerate were just as effective as oral prednisone in controlling asthma. But it must be remembered that when, despite regular therapy with inhaled corticosteroid, severe exacerbations of asthma occur, patients will need short high-dosage courses of systemic corticosteroids : to be effective the inhaled drug must reach its site of action and it cannot do so in the presence of severe airways obstruction. The
physicians taking part
in the trial
Aberdeen, Dr J. A. R. Friend; Abergavenny, Dr G. 0. Thomas; Aylesbury, Dr Elizabeth Hills and Dr Margaret Wolfendale; Balham, Dr Elizabeth Hicks, Dr F. J. Millard, and Dr D. E. Stableforth; Bangour, Dr J. Hope and Dr K. Murray; Bath, Dr A. Tanser; Bristol, Dr A. T. M. Roberts; Brompton, Dr J. Paterson; Cardiff, Dr N. G. Sanerkin, Dr A. Seaton, and Dr D. A. Williams; Colchester, Dr M. A. H. Awwad, Dr W. P. U. Kennedy, Dr J. A. Sampson, and Dr Uttara Vidysagar; Darlington, Dr C. K. Connolly; Doncaster, Dr H. C. Smyllie; Dundee, Dr D. A. Cook, Dr R. N. Johnston, and Dr D. H. Smith; Edinburgh, Dr 1. A. Campbell, Prof. J. W. Crofton, Dr. A. C. Douglas, Dr. D. A. Ellis, Dr. A. M. Hunter, Dr G. J. R. McHardy, Dr. W. G. Middleton, and Dr N. D. Olsen; High Wycombe, Dr Marguerite Black and Dr A. 0. Robson; Manchester, Dr Elsie M. Creighton and Dr T. Stretton; Newcastle upon Tyne, Dr M. J. B. Farebrother, Dr J. R. Lauckner, Dr P. 0. Leggat, and Dr E. A. Spriggs; Oxford, ’Dr R. Marshall and Dr A. I. Spriggs; Southampton, Dr H. Fraser, Dr R. C. Godfrey, Dr J. B. L. Howell, Dr W. M. Macleod, and Dr G. M. Sterling; Stoke-on-Trent, Dr K. Prowse; Sunderland, Dr S. Nariman;’Watford, Dr J. H. Angel and Dr Jean Morris. Their participation is
gratefully acknowledged, as is the help of Mrs P. Hindshaw, Mrs L. Hunt, and Mrs C. P. Davison. We thank Glaxo Laboratories Ltd. and Allen and Hanburys Research Ltd. for generous financial support and Dr C. H. Dash, Dr D. M. Harris, and Mr A. G. Butler for their helpful cooperation. The advice of Prof. V. H. T. James was much appreciated. Requests for reprints should be addressed to Dr I. A. Campbell, Plymouth General Hospital, Greenbank, Plymouth,
IDIOPATHIC PARKINSONISM TREATED WITH BROMOCREPTINE
D. B. CALNE P. F. TEYCHENNE P. N. LEIGH J. K. GREENACRE A. PETRIE J. L. REID A. N. BAMJI
Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London, and Laboratory of Neuropharmacology, National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, U.S.A. The
efficacy and toxicity of bromocriptine, a drug which simulates dopamine, have been studied in twenty-eight patients with idiopathic parkinsonism. A double-blind, withinpatient comparison between maximum tolerated doses of bromocriptine (mean 46·9 mg daily) and placebo revealed a substantial and statistically significant therapeutic response to the active drug. Adverse reactions were dose dependent, reversible, and similar to those encountered with levodopa. While taking bromocriptine fourteen patients were able to stop levodopa (with or without carbidopa); in five patients the dose of levodopa was reduced by 54% (mean). Eight patients could not tolerate bromocriptine; one patient failed to comply with prescribed adjustments of dosage. Summary
THEREhas lately been an increasing recognition- of the widespread distribution of dopaminergic receptors in tlle nervous system and the role of dopamine as a neurotransmitter. Bromocriptine, an ergot alkaloid containing a lysergic-acid residue and a tripeptide moiety, activates dopaminergic receptors in rats.S This finding led to the successful use of bromocriptine in conjunction with levodopa in parkinsonism.3 Subsequently, in a limited investigation of five patients, levodopa
entirely replaced by bromocriptine
without evidence of neurological deterioration or serious adverse effects.4 In view of these results we have undertaken a more extended double-blind study to assess the potency of bromocriptine as a therapeutic agent in the treatment of parkinsonism. Two other dopaminergic agonists, apomorphine and
piribedil,have previously been investigated 5- 8; although therapeutic activity was found, adverse reactions precluded their use in routine treatment. We report here more encouraging results with bromocriptine.
Patients and Methods
REFERENCES 1. British Thoracic and Tuberculosis Association. Brit. J. Dis. Chest (in the press). 2. James, V. H. T., Landon, J. Hypothalamic-Pituitary-Adrenal Function Tests; p. 17. Ciba Laboratories, 1970. 3. Morrow Brown, H., Storey, G., George, W. H. S. Br. med. J. 1972, 4.
5. 6. 7. 8. 9. 10.
i, 585. Clark, T. J. H. Lancet, 1972, i, 1361. Dash, C. H. Postgrad. med. J. 1974, Sept. suppl., p. 73. Gaddie, J., Petrie, G. R., Reid, I. W., Sinclair, D. J. M., Skinner, C., Palmer, K. N. V. Lancet, 1973, i, 691. McAllen, Monica K., Kochanowski, S. J., Shaw, K. M. Br. med. J. 1974, i, 171. Riordan, J. F., Dash, C. H., Sillett, R. W., McNicol, M. W. Postgrad. med. J. 1974, Sept. suppl., p. 61. Frears, Janna F., Wilson, Lyn C., Friedman, M. Archs Dis. Childh. 1973, 48, 856. Taylor, B., Norman, A. P. Postgrad. med. J. 1974, Sept. suppl., p. 44.
Twenty-eight patients with idiopathic parkinsonism were admitted to the study, but nine dropped out. Informed consent was obtained from all patients, who were warned that temporary deterioration in symptoms could be expected at some time. The mean age of the nineteen patients who remained in the study was 63 years (range 53-81); there were thirteen men and six women. All were on maximum tolerated doses of levodopa, with or without carbidopa. Design The study was performed in three consecutive stages: (1) bromocriptine was gradually introduced while reducing the dose of levodopa ; (2) the maximum tolerated dosage of