ARLS 2 1997 Astra Respiratory Literature Service Experts comments

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AstraZeneca Respiratory Literature Service
N°2 1997 (see N° 1 1997 also and N° 3 1997)

For many years, AstraZeneca Draco laboratories have brought to the asthmolgist community an excellent "Respiratory Literature Service" (ARLS) with an alert to new references, selected summaries and comments by a group of experts. In 1997, AstraZeneca is extending this concrete service with Asmanet in order to take advantage of the Internet capabilities. The following comments have been edited ( HTML format) to smooth the reading with hypertext links to integrate the comment in the Asmanet server and the worldwide distributed library on asthma, such as : abstract of the commented paper, references as seen on Medline and others, author's e-mail ...

	Title	Authors	Journal	Reviewer
1	Effectiveness of fluticasone propionate	Wolfe J.D., Selner J.C., Mendelson L.M., et al	Clin Ther 1996	Dr Duncan Geddes
2	Comparison of budesonide via Turbohaler and fluticasone propionate via disc-inhaler	Venables T.L., Addlestone M.B., Smithers A.J., et al	Br J Clin Res 1996	Dr Duncan Geddes
3	The effect of the menstrual cycle on asthma presentations in the emergency department	Skobeloff E.M., Spivey W.H., Silverman R., et al	Arch Intern Med 1996	Dr Duncan Geddes
4	The effect of the menstrual cycle on asthma presentations in the emergency department	Skobeloff E.M., Spivey W.H., Silverman R., et al	Arch Intern Med 1996	Professor Philippe Godard
5	Effects of prednisolone on bone turnover in patients with corticosteroid resistant asthma	Lane S.J., Vaja S., Swaminathan R., Lee T.H.	Clin Exp Allergy 1996	Professor Philippe Godard
6	Effectiveness of fluticasone propionate in patients with moderate asthma: a dose-ranging study	Wolfe J.D., Selner J.C., Mendelson L.M., et al	Clin Ther 1996	Professor Philippe Godard
7	Effects of prednisolone on bone turnover in patients with corticosteroid resistant asthma	Lane S.J., Vaja S., Swaminathan R., Lee T.H.	Clin Exp Allergy 1996	Professor John H. Toogood
8	A risk-benefit assessment of methotrexate in cortico-steroid dependent asthma	Shulimzon T.R., Shiner R.J.	Drug Safety 1996	Professor John H. Toogood

AstraZeneca Draco laboratories is also supporting the European Federation of Asthma and Allergy Associations which can be seen at http://www.efanet.org/

Access to Medline through Healtgate : direct access to the abstract whenever it's available is not possible. You have to perform a "search" using the "Healthgate Free Medline" search engine (and be exposed to the local advertiser banner which sort-of pays for the free access). You will then go through the following steps :

Select the names of the first two authors and do a "copy" (ctrl C on a PC under Windows) so that you will have the search key at hand.
Click on the link in order to get the Healthgate Medline search home page.
Paste the search key (ctrl V) into the search window displayed on your screen and perform the search.

Healthgate search engine will send you back the list of papers with those two authors. You will then select the link which you want if the paper is known to to Healthgate and click on the link to get the abstract.

...

1 Effectiveness of fluticasone propionate in patients
with moderate asthma: a dose-ranging study

When a number of different studies by a range of investigators in a variety of different countries come up with the same answer, the evidence becomes highly reliable. This dose-ranging study of fluticasone propionate in moderate asthma shows nothing new but is nevertheless important in guiding prescribing. Three-hundred-four patients with asthma, which had been present for at least six months and which was being treated with inhaled corticosteroids and beta-agonists, were assigned to receive placebo or fluticasone propionate 100, 250 or 500 mg twice daily via pMDI. All the measures showed a benefit from fluticasone but there was no difference between the three different dose groups. The measures included spirometry, peak flow monitoring, symptom scores, rescue bronchodilator usage and physician assessments.

These data support the use of inhaled corticosteroids and once again indicate that the dose response relationship is very flat with the vast majority of patients achieving maximum benefit at 100 mg twice daily. There is only seldom justification for higher doses with attendant risk of side effects. Many patients are still taking more than they need.

2 A comparison of the efficacy and patient acceptability of once daily budesonide via Turbohaler and twice daily fluticasone propionate via disc-inhaler at an equal daily dose of 400 mg in adult asthmatics

Venables T.L., Addlestone M.B., Smithers A.J., et al
Br J Clin Res 1996; 7: 15-32

This general practice study compared the effect of different inhaled corticosteroid regimens and found no important difference between budesonide 200 mg twice daily (Turbuhalerâ), budesonide 400 mg nocte (Turbuhaler) and fluticasone propionate 200 mg twice daily (disc-inhaler system). The study has reasonable power with 230 patients completing the randomised trial.

This is an example of a trial which provides real life information about what happens to asthma during routine prescribing in family practice but is also open to serious misinterpretation. In the first place, the patients had relatively mild asthma and may well have been optimally treated at lower doses of inhaled steroids than those used, so making a "no difference" result invalid. Secondly, the Turbuhaler and the disc-inhaler device have different drug delivery characteristics and so a true dose comparison cannot be made. Third, the study medication was taken for only eight weeks which is not long enough to assess exacerbation rates.

Nevertheless, the confirmation of the finding that once-daily treatment may be as good as twice daily is useful. The common sense message is that inhaled corticosteroids are a good treatment and in mild asthma it does not make very much difference which drug, delivery device, or dosing regimen is chosen.

3 The effect of the menstrual cycle on asthma presentations
in the emergency department

Seventy-five per cent of adult patients admitted to hospitals for asthma are women. This study demonstrates a nearly four-fold variation in asthma presentations by women during the perimenstrual intervals (days 26 to 4) when serum estradiol levels decrease sharply. The duration of the attack, the peak flow rate, the proportion needing admission to hospital and the use of bronchodilators were equivalent in all the groups studied (based on phase of menstrual cycle), but surprisingly the postovulatory women were slightly less likely to be treated with corticosteroids.

The relationship between menstrual cycle and asthma has been postulated before but this is one of the few adequately controlled studies to confirm the association. This study is in line with some observations of changes in smooth muscle sensitivity with female sex hormones but does not provide new data on mechanisms. There is a small literature suggesting that hormone manipulation might help some individuals with severe unstable asthma but good evidence is still lacking.

4 The effect of the menstrual cycle on asthma presentations
in the emergency department

Daily clinical practice, epidemiological surveys and several papers in the literature demonstrate that premenstrual asthma does exist. But the pathophysiological, clinical and therapeutic knowledge is still lacking.

Acute severity of premenstrual asthma: The authors of this paper did not observe any difference in the acute severity of asthma exacerbation in relation to phase of the menstrual cycle, as measured by duration of attack, PEF, admission - discharge ratio and treatment, except for steroids. However, they did not study the chronic severity of the women´s asthma. Some years ago we studied several women with premenstrual exacerbation of asthma; they were dependent on corticosteroids (1). During a 9-month follow-up period several of the women were admitted to hospital for exacerbation; one died.

Pathophysiology: The study results are interesting, as at least, two pathophysiological hypotheses can be proposed:

Treatment of premenstrual asthma: According to the previous observation, sensitivity to corticosteroids should be evaluated during the hormonal cycle.

1. Perrin B., Bousquet J., Michel F.B., Godard Ph., Jesuran M., Monabeka H, Bringer J.,
Severe premenstrual asthma
Lancet 1988; II: 843 - 4

Professor T.H. Lee and his group are conducting a long-term research program on corticosteroid resistant (CR) asthma. They have a clear definition of CR asthma and their results are very exciting.

It has been suggested that CR asthmatics could have less side effect of corticosteroids as compared to corticosteroid sensitive patients. That is the reason of this study. They chose to study serum and urine markers of bone turnover. They demonstrated without any doubt that the effect was identical in CR and corticosteroid sensitive patients. Their conclusion is clear: the risk for long-term side effects is equal.

However, this kind of experimental study only gives us a small piece of the puzzle. Long-term studies are required, associating clinical and biological observations.

Inhaled corticosteroids are effective in the treatment of asthma. There is no doubt about that. However, there are many controversies about one key issue; does a dose - response relationship exist?

In Europe, high-dose inhaled corticosteroides have been available for a long time. These doses are more effective than lower doses in certain patients and they are well tolerated. This is based on clinical experience.

The question is therefore why a study like this one does not demonstrate a dose - response relationship. In this study 200 mg/day fluticasone is equivalent to 500 mg/day and 1000 mg/day. The study has been well conducted, over three months; several parameters have been measured and statistical analysis seems to be correct.

I can find no clear answer to this apparent paradox. Results of this kind are important as they can have consequences for the strategy of treatment. The international guidelines suggest a stepwise approach for treatment; many experts suggest to start with an appropriate dose according to the severity and then to increase the dose if the efficacy is not sufficient. My own experience is to start with a higher dose to have a more rapid and complete effect and then taper the dose according to the level of asthma control. These two attitudes have to be validated in terms of long-term outcome, but also in terms of quality-of-life and cost-effectiveness.

This and related studies cited by the authors indicate that asthmatic patients who have sufficient chronic airflow limitation to materially limit their FEV1 responsiveness to corticosteroid therapy - and who may be deemed, in consequence, to be "corticosteroid resistant" - do not have a primary intracellular defect involving pulmonary and extrapulmonary systems that could explain their limited steroid responsiveness.

Fortunately, the failure of FEV1 to respond significantly to corticosteroid therapy does not necessarily preclude a clinically valuable reduction in asthma symptoms and disability (1, 2, 3). This reflects the fact that, in chronic asthma, airflow obstruction and symptom activity may correlate only weakly with one another (4).

In clinical practice, those patients who present as "corticosteroid resistant", actually reflect a very heterogeneous mix of causative factors, which requires an individualized (as opposed to a categorical) approach to diagnosis and management (5).

1. Toogood J.H., White F., Baskerville J., et al
Comparison of the antiasthmatic, oropharyngeal, and systemic glucocorticoid effects of budesonide administered through a pressurized aerosol plus spacer or the Turbuhalerâ dry powder inhaler
J Allergy Clin Immunol 1997; 99: 186-193

2. Toogood J.H., Baskerville J., Jennings B., et al
Bioequivalent doses of budesonide and prednisone in moderate and severe asthma
J Allergy Clin Immunol 1989; 84: 688-700

3. Toogood J.H., Baskerville J.
Methodology for demonstrating dose response of inhaled corticosteroids
J Aerosol Med 1995; 8: 129

4. Toogood J.H., Frankish C.W., Jennings B.H., et al
A study of the mechanism of the antiasthmatic action of inhaled budesonide
J Allergy Clin Immunol 1990; 85: 872-880

Osteoporosis with fracture is the commonest major complication of chronic steroid dependency in asthmatic patients (1, 2, 3). Therefore, to establish the clinical importance, if any, of any reduction in steroid usage that may be achieved under the aegis of methotrexate therapy, it is necessary to document an accompanying reduction in the risk of fracture. This and similar reviews do not indicate that this has been done.

Because methotrexate has been reported to cause bone pain, osteoporosis and fracture (4), ethical considerations dictate that steroid-dependent patients committed to methotrexate be monitored by serial bone densitometry. In this way one may determine whether the ultimate outcome of the methotrexate plus steroid-weaning regimen on the risk of fracture turns out to be favourable or unfavourable.

1. Lukert B.P., Raisz L.G.
Glucocorticoid-induced osteoporosis: Pathogenesis and management.
Ann Intern Med 1990; 112: 352-364

2. Adinoff A.D., Hollister J.R.
Steroid-induced fracture and bone loss in patients with asthma
New Engl J Med 1983; 309: 265-268

3. Baskerville J., Hodsman A., Toogood J.H., et al
Associations of long term inhaled steroid (I-S) and oral prednisone (PRED) therapy with vertebral fracture in asthmatic adults
J Allergy Clin Immunol 1994; 93: 200 (abstract)

4. Jones G., Sambrook P.N.
Drug-induced disorders of bone metabolism. Incidence, management and avoidance
Drug Safety 1994; 10: 480-489

Asmanet

Congrès Conçue et réalisée par: Michel Godard (at)

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Date de création: 1997 - Dernière mise à jour: 17/06/99
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