Table Of ContentTHE ROLE
of
BETA RECEPTOR
AGONIST THERAPY
in
ASTHMA MORTALITY
Taylor & Francis
Taylor & Francis Group
http:// taylorandfrancis.com
THE ROLE
of
BETA RECEPTOR
AGONIST THERAPY
•
ln
ASTHMA MORTALITY
Edited by
Richard Beasley
Neil E. Pearce
Boca Raton London New York
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FOREWORD
I feel honoured to have been invited to introduce this excellent monograph
which surveys and analyzes the nature, actions, and unwanted actions of one
of the most widely used class of drugs in respiratory medicine — the beta
agonists.
Until recently there were few reasons to question their basic safety; after
all their actions are only part of the wider actions of adrenaline. Further,
following the introduction of corticosteroids and cromoglycate, the emphasis
on reversible airflow obstruction as the essence of asthma was overtaken by
the concept of bronchial inflammation. Indeed, deaths from asthma are fre-
quently attributed to inadequate use of corticosteroids, and protocols of therapy
have been based on this assumption.
The introduction of the new, powerful, beta2 agonist, fenoterol, together
with the relatively high (though still low) death rate from asthma in New
Zealand, led to revival of suspicion that these drugs might be responsible.
The problems of investigating such a suspicion were formidable: a disorder
with no agreed operational definition, high prevalence, and a wide range of
severity; a drug with few side effects other than the suspicion of a very low
incidence of death; the usual treatment regimen included self-administration;
there was often poor documentation of the events preceding the death. Further,
confirmation of these suspicions would have implications not only for the
treatment of this common disorder, but for the drug regulatory authorities and
the pharmaceutical industry itself.
This monograph examines rigorously the many facets of this problem,
including the pharmacology of beta agonists, their clinical usage, epidemi-
ological aspects of asthma and its treatment, and epidemiological method-
ology. While an immediate contribution will be to the clinical management
of asthma, on which it is likely to have a profound effect, its ultimate influence
will be far wider. By addressing a situation that has many parallels in medicine,
it has contributed to their better understanding and their solution.
As Popper has made clear, nothing in science is capable of proof, only
disproof. Beasley, Pearce, and colleagues have marshalled the evidence to
incriminate fenoterol in the increased death rate from asthma in New Zealand
in the 1970s, as well as reviewing evidence linking another beta agonist
(isoprenaline forte) to the epidemics of the 1960s, and raising more general
questions about the efficacy and safety of this class of drug. The burden now
lies with those who would disprove this hypothesis. Unless or until this
happens, no longer will clinicians be able to prescribe these drugs as if their
only effect is their undoubted symptomatic benefit.
The editors and contributors, in tackling a specific problem, have illu-
minated a much wider area of medicine from which the full benefits are yet
to be derived. They have earned our congratulations and our thanks.
J. B. Howell
Emeritus Professor of Medicine
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PREFACE
Asthma is one of the few treatable diseases in which there has been a
widespread increase in reported morbidity and mortality over recent decades.
These adverse trends have occurred despite major increases in our knowledge
and understanding of the pathophysiology of the disease, improved diagnostic
awareness, and the availability of more potent and specific forms of therapy.
In this context, it is important to consider whether some aspects of our current
management may be adversely affecting the natural history of the disease.
In this book, the possible role of beta-agonist therapy in asthma mortality
is critically reviewed. An attempt has been made to produce a comprehensive
overview of existing knowledge, bringing together relevant information that
has been published in many different journals, covering a wide range of
disciplines. This multidisciplinary approach spans the fields of epidemiology,
pharmacology, clinical medicine, and public health. It includes an historical
perspective and sections on experimental and epidemiological methods for
examining .the possible relationship between beta-agonist therapy and asthma
mortality. The authors of the chapters in this book are internationally rec-
ognized experts in their fields, and have all made major contributions to our
understanding of these issues.
Although this has been a controversial area, it is pleasing that the con-
troversy has led to further research, the results of which have improved our
understanding of beta-agonist therapy, and the way in which it should be used
in the management of asthma. However, as highlighted in this book, there
are still many unanswered questions that will need to be resolved through
further research.
It is always difficult to decide when it is the right time to prepare such
a book. However, we felt that it was important that existing scientific evidence
is reviewed at this stage, in this rapidly expanding field. Unfortunately, a
review of the possible role of the many nonpharmacological factors that may
have contributed to the increase in prevalence, morbidity, and mortality from
asthma was beyond the scope of this book. Likewise, recommendations for
the therapeutic use of beta-agonist drug treatment are not addressed in this
book, but they are well covered in many other texts on asthma.
We hope that this book will be of interest to clinicians, pharmacologists,
epidemiologists, and all those interested in addressing the problems of in-
creasing asthma morbidity and mortality.
Richard Beasley, M.D.
Neil Pearce, Ph.D.
THE EDITORS
Richard Beasley, M.D., is Professor of Medicine at the Wellington
School of Medicine, University of Otago Medical School and Consultant
Physician at Wellington Hospital, Wellington, New Zealand.
Dr. Beasley graduated in 1979 from the University of Otago Medical
School with an MBChB degree and became a fellow of the Royal Australasian
College of Physicians in 1985. He then took up a New Zealand Medical
Research Council-Wellcome Trust Research Fellowship at the University of
Southampton, United Kingdom, before returning to the Wellington School
of Medicine in 1987 and was appointed to the Chair of Medicine in 1993.
He was awarded his M.D. degree from the University of Southampton in
1990, and returned to that institution as a Medical Research Council (U.K.)
Visiting Senior Scientist in 1992.
Dr. Beasley is a member of the American Thoracic Society, British Tho-
racic Society, European Respiratory Society, Thoracic Society of Australia
and New Zealand, and the Collegium Internationale Allergologicum. He is
President of the Australian Chapter of the International Association of Asth-
mology and has served on a number of advisory committees including the
Expert Panel of the FDA Pulmonary-Allergy Drugs Advisory Committee.
Dr. Beasley is author of more than one hundred papers in the medical
literature. His current major research interests in the field of asthma are related
to epidemiology, pharmacology, and management.
Neil Pearce, Ph.D,, is a Senior Research Fellow in the Department of
Medicine in the Wellington School of Medicine. Dr. Pearce obtained his
training at the Wellingtoi School of Medicine, completing his Ph.D. degree
in epidemiology in 1985 From 1985 to 1987 he carried out epidemiological
research in the Departim nt of Epidemiology, University of North Carolina
at Chapel Hill, funded by an Overseas Research Fellowship of the Health
Research Council of New Zealand.
Since 1987 he has primarily carried out teaching and research in epide-
miology at the Wellington School of Medicine, but during 1992 to 1993 he
is based at the International Agency for Research on Cancer in Lyon, France,
was recipient of a Visiting Scientist Award. He is currently engaged in full-
time epidemiological research in the Wellington School of Medicine with
funding from the Health Research Council of New Zealand; his asthma
epidemiology research is conducted as a member of the Wellington Asthma
Research Group (directed by Drs. Beasley, Burgess, Crane, and Pearce),
which is funded by a Programme Grant from the Health Research Council of
New Zealand.
Dr. Pearce is a member of the Australasian Epidemiology Association,
the International Epidemiology Association, the International Society for
Pharmacoepidemiology, the Society for Epidemiologic Research, and the
Thoracic Society of Australia and New Zealand. Dr. Pearce has co-authored
a textbook of occupational epidemiology, and more than one hundred papers.
His current major research interests include asthma epidemiology, occupa-
tional and environmental epidemiology, cancer epidemiology, and epidemi-
ological methods.
