Bronchodilator treatment and deaths from asthma: case-control study
BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.38316.729907.8F (Published 13 January 2005) Cite this as: BMJ 2005;330:117All rapid responses
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To the Editor:
Anderson et al. (1) fail to mention the possible importance of the close association of beta agonists with the use of inhaled corticosteroids. This has been reported in research performed on the UK General Practice Research Database (2), which showed that short acting beta agonists overusers were more likely to overuse corticosteroids.
This dual overuse has its own dangers, one of them being the critical role of compliance. In one study (3), electronically measured adherence to corticosteroids dropped to approximately 50% within seven days of hospital discharge, followed by a significant worsening in symptom control. The proinflammatory activity of the albuterol distomer (4), unopposed by corticosteroids, might be a contributory mechanism for the deleterious effects and increased risk of death from asthma in dual users who are not compliant.
There are many reasons for noncompliance. One of them may be adverse effects like cough and dizziness, which may prevent further inhalation, leading to a pattern of intermittent treatment with both agents. Another pattern of non-compliance may be to increase the beta-agonist use, while failing to use inhaled corticosteroids, with an increased risk of asthma death.
REFERENCES
1. Anderson HR, Ayres JG, Sturdy PM, Bland JM, Butland BK, Peckitt C, et al. Bronchodilator treatment and deaths from asthma: case-control study. BMJ. 2005 Jan 15;330(7483):117. Epub 2004 Dec 23.
2. Lanes SF, García Rodríguez, LA, Huerta C. Respiratory medications and risk of asthma death Thorax 2002;57:683-686.
3. Krishnan JA, Riekert KA, McCoy JV, Stewart DY, Schmidt S, Chanmugam A, et al. Corticosteroid use after hospital discharge among high-risk adults with asthma. Am J Respir Crit Care Med. 2004 Dec 15;170(12):1281-5. Epub 2004 Sep 16.
4. Agrawal DK, Ariyarathna K, Kelbe PW. (S)-Albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells. J Allergy Clin Immunol. 2004 Mar;113(3):503-10.
Competing interests:
None declared
Competing interests: No competing interests
This article was very interesting. It concerns me that the level of
inhaled steroid use in both index cases and controls appears low (approx
58% 3 months before death). It is my practice when patients with asthma
are using a short-acting beta agonist more than 1-2 times a day for most
days of the week to prescribe an inhaled steroid to be used every day.
Could an explanation for the perceived dangers of short acting beta-
agonists include the reluctance of many people with asthma to use inhaled
steroids regularly? A serious problem with this study is the difficulty
in matching prescription records with actual usage. It is often said that
while patients will get their prescription to please their doctor, they
often do not use the prescription. The evidence of this is found in
"brown bag" reviews where patients bring unused medicines to the chemist
when they renew their prescription.
I am interested in the chimera of beta agonist forumlations, but the
reported susceptibility to deterioration in lung function only affects a
few people with asthma in my practice. Many patients are grateful for the
relief salbutamol brings, while only a few patients seem not to tolerate
this agent.
Lastly, this sort of study while important, does not give space to
individual factors affecting asthma control such as anxiety states,
overbreathing syndrome nor the use of breathing techniques (eg Buteyko
method). It may be of interest to discover if there is a personality type
or breathing pattern which influences the response to beta agonists
specifically, and overall asthma control generally.
Competing interests:
I have asthma and use salmeterol and Qvar every day
Competing interests: No competing interests
The statement made by both Anderson et al [1] and the British Medical
Journal [1] that long-acting beta2-agonist does not increase the risk of
death is not entirely accurate. In a large placebo-controlled study
consisting of 26,353 patients with asthma, it was found that salmeterol
significantly increased the number of respiratory and asthma related
deaths and life-threatening experiences in African-Americans [2].
Consequently, the potential threat of long-acting beta2-agonist remains
and will require further prospective evaluation.
References
1. Anderson HR, Ayres JG, Sturdy PM, Bland JM, Butland BK, Peckitt C,
Taylor JC, Victor CR. Bronchodilator treatment and deaths from asthma:
case-control study. BMJ 2005;330:117-20.
2. Rickard KA. SMART safety study (data on file). Research Triangle
Park (NC), USA: GlaxoSmithKline; 2003. Available at:
http://www.fda.gov/medwatch/SAFETY/2003/serevent_deardoc.pdf
Competing interests:
None declared
Competing interests: No competing interests
My appreciation goes to George Strube for his helpful response. Too
bad he's retired - for we asthmatics, that is!
The Finnish approach seems eminently sensible and yet simple. I would
think this message could easily be communicated to asthma patients in the
UK.
Even better for me would be to pay a (long) visit to a third-world
tropical country where my asthma and eczema tend to disappear.
Competing interests:
None declared
Competing interests: No competing interests
The short answer to Gareth Lloyd's question is "yes". This was
studied in 1993(1) and showed rebound bronchial hyperreactivity following
inhalation of a short acting B-agonist. This drug has no anti-
inflammatory effect so that the bronchial inflammation persists. When the
bronchodilator effect has passed, symptoms return and may even be worse.
Further inhalations are then required and the patient can become dependent
on this drug. This cycle can only be broken by stopping the B-agonist
and/or using steroids to treat the underlying inflammation. This is
consistent with his own experience.
Malcolm Sears has published an excellent summary of the asthma
saga(2) where he emphasises that short acting B-agonists should only be
used as needed for occasional sypmtom relief and not for maintenance
therapy in asthma.
The BTS/SIGN guidelines recommend this in their step1 but it is very easy
for patients to try to use this more frequently for maintenance and so
avoid the use of inhaled steroids which would give better control (step2)
The use of inhaled steroids as soon as the diagnosis of asthma has
been confirmed avoids this pitfall: regular inhaled coticosteroids are
used for maintenance with occasional use of short acting B-agonists for
breakthrough wheezing. This approach has been evaluated and adopted in
Finland with great success (3)
As a science jounalist, why not pay a visit to Finland to see what is
going on?
References
1 Wahedna et al. Asthma control during and after cessation of regular
B-agonist treatment. Am. Rev Respir Dis 1993;148:707
2 Lancet;Commentary May 13, 2000 p1658-9
3 Asthma programme in Finland. T Haahtela et al. Thorax 2001; 56:806
-814
Competing interests:
None declared
Competing interests: No competing interests
Sir,
The analysis of bronchodilator treatment and deaths from asthma by
Anderson et al. is important for the positive association the authors
note between mortality and short acting b2-agonist use. However, the
authors did not include any data regarding patients simultaneously
taking b blocking agents in their paper.
While beta-blockers are contraindicated for asthma, a number of such
patients have been prescribed beta-blockers for conditions such as
hypertension, ischemic heart disease, atrial fibrillation and heart
failure. More recently studies in mice have shown that although
b-blocking agents initially make asthmatic lungs more prone to
bronchospasm, continuing treatment in fact makes them less sensitive to
Attacks.1 As a result, recruitment is now under way for a clinical
trial of nadolol in asthmatic patients.2 Furthermore, beta-blocking
agents have been shown to have pronounced effects on mortality rates in
those who suffer from both obstructive lung disease and ischaemic heart
disease.3
Are the authors able to provide a subgroup analysis on those patients
also taking beta-blockers? An attempt to draw an association between
beta-agonist use and mortality would, in our view, be more complete with
this data.
1) Callaerts-Vegh Z, Evans KL, Dudekula N, Cuba D, Knoll BJ, Callaerts PF,
Giles H, Shardonofsky FR, Bond RA.
Effects of acute and chronic administration of beta-adrenoceptor ligands on
airway function in a murine model of asthma.
Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):4948-53.
2) Abbott A.
Beta-blocker goes on trial as asthma therapy.
Nature. 2004 Nov 4;432(7013):7.
3)Chen J, Radford MJ, Wang Y, Marciniak TA, Krumholz HM.
Effectiveness of beta-blocker therapy after acute myocardial infarction in
elderly patients with chronic obstructive pulmonary disease or asthma.
J Am Coll Cardiol. 2001 Jun 1;37(7):1950-6.
Competing interests:
None declared
Competing interests: No competing interests
Editor - Anderson et al [1] fruitfully highlight the possibility of a
causal relationship between use of short-acting beta-sympathomimetic drugs
and asthma morbidity and mortality. Many reasons for the association
between the use of beta-sympathomimetics and increased mortality have been
suggested. Of these, the possible effects of how these medications are
formulated have not been adequately studied.
Beta-sympathomimetics have historically been supplied as the racemic
mixture, that is a 50:50 mixture of the eutomer and distomer. However,
numerous preclinical and in vitro studies have indicated that the distomer
is not an inert isomer, but may have pro-inflammatory effects [2]. More
recently, trials in which the pure eutomer has been given to both adult
and paediatric patients have indicated that those treated with the eutomer
required less medication, had shorter lengths of hospital stay, had
decreased costs for nebulised therapy and hospitalisation and appeared to
have a more prolonged therapeutic benefit [3,4].
Although the evidence behind this chiral switch has been disputed,
mainly by the results of short, crossover studies [5], one should keep in
mind that the studies that have addressed this issue have been short-term
studies which have not investigated long-term consequences or chronic use.
We believe that this issue merits a direct comparison of eutomer with the
racemic mixture in adequately powered (multicentre) randomised-controlled
trials. Such trials should last months or years, be community based and
include the whole age-range of people treated for bronchial hyper-
responsiveness.
References:
1. Anderson HR, Ayres JG, Sturdy PM, et al. Bronchodilator treatment and
deaths from asthma: case-control study. BMJ 2005; 330: 117-120.
2. Costello JF. Sympathomimetic enantiomers in the treatment of asthma.
The Parthenon Publishing Group, 1995.
3. Nowak R. Single isomer levalbuterol: a review of the acute data. Curr
Allergy Asthma Rep 2003; 3: 172-178.
4. Truitt T, Witko J, Halpern M. Levarbuterol compared to racemic
albuterol: efficacy and outcomes in patients hospitalized with COPD or
asthma. Chest 2003; 123: 128-135.
5. Boulton DW, Fawcett JP. Beta2-agonist eutomers: a rational option for
the treatment of asthma? Am J Respir Med 2002; 1: 305-311.
Competing interests:
None declared
Competing interests: No competing interests
This useful research understandably measures that which is easiest to
measure - death rates.
However, it would be very interesting if a subtle extension to this
research could be conducted; to ascertain whether beta-agonists (long and
short-term) make the *underlying* condition of an asthmatic worse.
I suffer from asthma and after long experience have found that beta-
agonists weaken the underlying robustness of my respiration. Sure, they
give short-term relief and salmeterol is useful once in a while if I've
been near cats or cigarette smoke. But if taken every day, as the local
asthma nurse ecommends, then I *need* them every day and will be in a bad
way if I miss the daily fix. Even one puff means the next day I will feel
a bit short of breath and the temptation then is to take another puff that
day and
so the addiction is rapidly descended into.
However, with just steroid inhalers and a bit of patience as I withdraw
from the beta-agonists, I find my asthma improves without them. I have two
asthmatic friends who have found exactly the same thing.
It would be very useful if these anecdotal findings could be investigated
scientifically.
Competing interests:
None declared
Competing interests: No competing interests
Hypokalemia-induced arrhythmia – the assassin in beta 2 agonist treated patients?
Anderson et al. confirmed in a large-scale study that inhaled short
acting beta2 agonists are associated with increased mortality in asthma.
This effect was confined to patients above 45 years and was not seen for
long acting beta2 agonists. A tendency to increased mortality was also
seen in patients treated with oral methylxanthines. Doses of the drugs –
and regarding the short acting beta2 agonists – doses taken immediately
before death – were unknown. Mechanisms of death were not assessed. No
physiological or pharmacological explanations for the findings were
discussed. We speculate that this adverse effect is caused by fatal
arrhythmia.
beta2 agonists stimulate the Na,K-pump imbedded in the cell membrane.
This stimulation is achieved through several steps – including raised cAMP
levels. Thus, because methylxanthines increase cAMP level these drugs will
also stimulate the Na,K-pump. Pump stimulation causes an immediate
cellular influx of potassium (K), which reduces extracellular K and lowers
plasma K. Plasma K reductions of ~0.5 mM have been reported for standard
beta2 agonist doses. However,
patients suffering from an acute severe attack may take repeated short
acting beta2 agonist doses leading to a more pronounced drop in plasma K.
The often-severe stress characterizing patients with acute attacks is
associated with a catecholamine surge, which also tends to lower plasma K.
Therefore plasma K values may be reduced from 4 mM to maybe as low as ~2
mM within a few minutes during an asthmatic attack. Through the
paradoxical conduction response of the myocardial HERG K channel this will
lead to prolongation of the repolarisation phase in the heart, and prolong
the QT interval. This will be more pronounced in patients with
preexcisting hypokalemia (malnourished patients or patients treated with
methylxanthines or diuretics – often used in COPD) and in patients with
otherwise subclinical QT prolongation. Another group at risk would be
patients simultaneously treated with QT prolonging drugs, - in the present
context erythromycin and certain antihistamines would be of specific
concern. QT prolongation favours development of ventricular tachycardia or
ventricular fibrillation – and death - a risk that increases with age.
On this basis we suggest that Anderson et al. or others with access
to large patient populations assess this hypothesis. This would be of
obvious importance for safety reasons and in order to establish a way to
circumvent this serious adverse effect of short acting beta2 agonists.
Avoidance of K depletion and hypokalemia and certain drug combinations –
and maybe in a subset of patients – administration of K supplementation or
aldosterone antagonists might prove lifesaving.
Competing interests:
None declared
Competing interests: No competing interests