(Chest. 2000;117:67S-69S.)
© 2000
American College of Chest Physicians
The Future for Tiotropium*
Peter M. A. Calverley, MD
*
From the University Hospital, Aintree, Liverpool, UK.
Correspondence to: Peter M. A. Calverley, MD, Pulmonary and Rehabilitation Research group, University Clinical Department at Aintree, University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, UK; email: PMACAL{at}liverpool.ac.uk
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Abstract
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In spite of growing interest in and knowledge about the causes and
progression of COPD, neither the assessment nor pharmacologic treatment
of this condition is currently ideal. Tiotropium is the first new
treatment for COPD in many years. Tiotropium is a long-acting
anticholinergic agent that has a potential role as a once-daily
maintenance treatment, and a picture of its effectiveness is gradually
emerging. Spirometry data from clinical studies demonstrate that it is
a potent bronchodilator in patients with COPD and it is very well
tolerated. Further data on health status and quality of life are
awaited.
Key Words: anticholinergic agents • bronchodilator therapy • COPD • health-related quality of life • tiotropium
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Introduction
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Our
knowledge of COPD has increased enormously in recent years, as has our
growing appreciation of its importance in both the developed and
developing world. The preceding articles in this supplement give some
insight into the current status of the management of COPD and provide
guidance about the kind of information needed for placing tiotropium in
context among the various treatment recommendations.
A number of articles have discussed the multinational management
guidelines that provide useful approaches to the treatment of
COPD.1
In general, the guidelines offer similar
advice with some local variation often reflecting the audience to which
they are being addressed. For example, the European Respiratory Society
Guidelines address almost everyone from general physicians to
respiratory specialists.2
In contrast, the American
Thoracic Society guidelines are very much directed toward the
respiratory specialist,3
and the British guidelines are
trying to reach general practitioners.4
The aims of the
Global Initiative for Chronic Obstructive Lung Diseases are laudable,
and the project members want to make management recommendations that
are applicable globally in many different health care
environments.5
Like all guidelines, the Global Initiative
for Chronic Obstructive Lung Diseases guidelines will look carefully at
new drugs such as tiotropium. Although guidelines are not mandatory and
provide guidance only, in a world where costs are important, people
will seek guidance as to what is and what is not reasonable treatment.
Current treatment guidelines emphasize the role of spirometry in the
diagnosis of disease, but there is now increased understanding of its
limitations in assessing the choice of treatment. A strong message from
articles in this supplement is that we should not rely solely on
FEV1 when assessing new drugs. O’Donnell’s
article6
explains the physiologic basis of the major
symptom of patients with COPD—breathlessness—and shows why small
spirometric changes can translate into important improvements in
exercise performance and clinical well being. Therefore, it may be
important to consider the changes in end-inspiratory lung volume as
well as end-expiratory lung volume. Mahler7
describes the
importance of assessing symptoms as an outcome measure. For example,
improving breathlessness may have a significant effect on the
patients’ quality of life (QoL).7
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Current Pharmacologic Treatment of COPD
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Among the desirable attributes of any pharmacologic treatment for
COPD is face validity, ie, there should be a rationale for
using a drug in a particular condition combined with appropriate
pharmacologic properties. COPD patients often have comorbidities and
are taking other treatments, so drug interactions must be avoided.
Hence, a drug for COPD should have low bioavailability and should be
targeted to where it is needed in the airways. It is almost
self-evident that a drug with a long duration of action has
considerable advantages in both preventing symptoms developing and also
in simplifying the treatment regimen. In terms of dosing and
compliance, a good administration device is needed that is liked by the
patients. Finally, a different mode of action from other treatments
might further improve outcome for these disabled patients.
Do current treatments possess these attributes? Anticholinergic drugs
certainly have some face validity. In our laboratory, we have recently
shown that in patients with very severe COPD who were treated with
ipratropium bromide there was a significant fall in resting airways
resistance (June 1999; unpublished data). Interestingly, when
these patients breathed cold air (the bronchoconstrictor effects of
which are mediated by cholinergic mechanisms) after ipratropium, there
was still some increase in resistance indicating that these people have
an intact cholinergic system. In other studies of short-acting inhaled
bronchodilators, there is some evidence of tachyphylaxis with a
ß2-agonist; but, in contrast, ipratropium and
the combination of ipratropium and a ß2-agonist
did not show this effect.8
There is some synergy between
anticholinergics and ß2-agonists, and it will
be interesting to see if this occurs with long-acting inhaled
ß2-agonists. Existing treatment does not
protect against bronchoconstriction beyond 6 h, but a recently
published large study compared salmeterol (twice daily) with
ipratropium (qid) and placebo, and showed that salmeterol had
long-lasting effects with a potent bronchodilator
profile.9
Pharmacologic mechanisms suggest that drugs
primarily acting on cholinergic receptors are unlikely to modify the
natural history of COPD, and this is supported by data from the Lung
Health Study that show that ipratropium did not modify the decline in
lung function characteristic of COPD patients.10
The desirable outcomes of drug treatment in COPD are primarily an
improvement in lung mechanics and gas exchange. We know relatively
little about the impact of modifying gas exchange ,but all
bronchodilators improve, by definition, lung mechanics. We also like to
think that these drugs reduce symptoms, improve exercise performance,
perhaps reduce the number of exacerbations, or even modify the disease
natural history.
Long-acting bronchodilators are now available for the treatment of
COPD. What benefits do these have on QoL? In the comparative
salmeterol/ipratropium study described earlier, QoL was similar in the
groups treated with ipratropium and salmeterol.9
However,
in another study, salmeterol showed a change beyond the clinically
significant level of four units in the St. George’s Respiratory
Questionnaire total score.11
In an initial report from the
ISOLDE (Inhaled Steroids in Obstructive Lung Disease in Europe)
study of severe COPD patients, inhaled corticosteroids when compared
with placebo, slowed down the rate at which health status deteriorated
and reached this level of four units over a 3-year
period.12
There was an acute improvement in QoL, but the
duration of effect is uncertain. Longer-term studies are going to be
needed with all of these agents to try and answer this question.
Exacerbations are a common problem that has been frequently ignored but
is now increasing in importance for economic and practical reasons.
Data from a retrospective study by Friedman et al13
showed
that comparing a combination of ipratropium and salbutamol with
salbutamol or ipratropium in a large number of patients with fairly
severe COPD resulted in a reduced number of exacerbations seen in the
combination group. The data set was not primarily acquired in
order for this hypothesis to be tested, so we need more studies to look
prospectively at the effect of drug treatment on exacerbations.
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Tiotropium
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Although existing treatments for COPD are undoubtedly helpful,
they are far from ideal and new treatments are needed.
Barnes14
has described the appropriate pharmacology of
tiotropium for the treatment of COPD. The 3-month clinical study
comparing tiotropium with placebo showed that tiotropium causes an
early improvement in FEV1, which is well
maintained.15
In the comparative study with ipratropium, a
significant benefit of tiotropium is seen at 6 h.16
Results from these studies indicate that the degree of bronchodilation
is at least as great as that seen with salmeterol, and direct
comparative studies will be of interest. We also need to look at other
end points not available from these studies, such as changes in health
status. At present, salbutamol rescue therapy use provides some early
useful information. Less salbutamol was used by patients receiving
tiotropium, suggesting that control of COPD was improved, and there
were fewer occasions where patients experienced sufficient ill health
to seek further therapy. Tiotropium had few side effects except dry
mouth, which was significantly more common than with placebo therapy.
In conclusion, tiotropium has face validity with appropriate
pharmacology for the treatment of COPD (Table 1)
.
Tiotropium is a very long-acting drug with an extremely simple
treatment regimen and low bioavailability. We do not know yet its
potential for synergy. In terms of outcome, tiotropium clearly improves
lung mechanics (Table 2)
.
Given what we know about ipratropium, it would be unlikely to impair
gas exchange by day or night, but results from sleep studies are
awaited and may give insight into the effect of this drug on sleep
quality. To date, there are no direct measurements of symptoms (in
particular health status and QoL), exercise tolerance, and effects on
exacerbations. We do not know how it compares with other therapies.
These are very interesting questions, and future data are eagerly
awaited. Ultimately, like any investigator at the end of a review like
this, I want more data and a longer follow-up on ever more patients. We
are charged with looking after patients who are sick, and we want to
make sure that when we recommend new drugs we really are giving them
the best treatment possible. In addition, we often first see people
with severe COPD only when they are admitted as an acute emergency in
the late stage of disease. Tiotropium will be given to patients like
this in an attempt to alleviate the considerable suffering and
distress, but I would like to think that we are going to develop ways
of seeing and diagnosing COPD earlier so that the benefits of
tiotropium therapy can be extended to other patients.
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Footnotes
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Abbreviation: QoL = quality of life
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References
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Ferguson, GT (2000) Recommendations for the management of COPD. Chest 117(suppl),23S-28S[Abstract/Free Full Text]
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Optimal assessment and management of chronic obstructive pulmonary disease (COPD): a consensus statement of the European Respiratory Society. Eur Respir J 1995; 8:1398–1420
-
Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease: ATS statement. Am J Respir Crit Care Med 1995; 152:S77–S121
-
Guidelines for the management of chronic obstructive pulmonary disease. Group of the Standards of Care Committee of the British Thoracic Society. Thorax 1997; 52:S1–S28
-
Pauwels, RA (2000) National and international guidelines for COPD: the need for evidence. Chest 117(suppl),20S-22S[Abstract/Free Full Text]
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O’Donnell, DE (2000) Assessment of bronchodilator efficacy in symptomatic COPD: is spirometry useful? Chest 117(suppl),42S-47S[Abstract/Free Full Text]
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Mahler, DA (2000) How should health-related quality of life be assessed in patients with COPD? Chest 117(suppl),54S-57S[Abstract/Free Full Text]
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In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest 1994; 105:1411–1419
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Mahler, DA, Donohue, JF, Barbee, RA, et al (1999) Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 115,957-965[Abstract/Free Full Text]
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Anthonisen, NR, Connett, JE, Kiley, JP, et al (1994) Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA 272,1497-1505[Abstract]
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Jones, PW, Bosh, TK (1997) Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 155,1283-1289[Abstract]
-
Spencer, S, Anie, K, Calverley, PMA, et al (1999) Rate of health status decline is reduced in COPD patients treated with fluticasone compared to placebo [abstract]. Am J Respir Crit Care Med 159,A522
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Friedman, M, Serby, CW, Menjoge, SS, et al (1999) Pharmacokinetic evaluation of a combination of ipratropium plus albuterol compared with ipratropium alone and albuterol alone in COPD. Chest 115,635-641[Abstract/Free Full Text]
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Barnes, PJ (2000) The pharmacological properties of tiotropium. Chest 117(suppl),63S-66S[Abstract/Free Full Text]
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Casaburi, R, Serby, CW, Menjoge, SS, et al (1999) The spirometric efficacy of once daily dosing with tiotropium in stable COPD [abstract]. Am J Respir Crit Care Med 159,A524
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Van Noord, J, Bantje, T, Eland, M, et al (1999) Superior efficacy of tiotropium compared to ipratropium as a maintenance treatment bronchodilator in COPD [abstract]. Am J Respir Crit Care Med 159,A525
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Abstract
Introduction
