Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Do beta-agonists make asthma worse?
- Gareth I Lloyd (14 January 2005)
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Another clue to an unanswered question
- Christos S Zipitis, Mark A. Turner (22 January 2005)
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Mortality Rates In Those Using Beta-Agonist and Beta-Blocking Agents
- Alistair C Lindsay, Ameet Bakhai Consultant Cardiologist (23 January 2005)
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Re: Do beta-agonists make asthma worse?
- George Strube (24 January 2005)
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Re: Do beta-agonists make asthma worse?
- Gareth Lloyd (25 January 2005)
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Clear and Present Danger: The Beta2-Agonist Saga
- Daniel K C Lee (27 January 2005)
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Benefit of inhaled steroids appear understated
- David Lewis (28 January 2005)
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Non-compliance in Dual Overusers May Lead to Death from Asthma
- Mihai S. Jalba, M.D., Ph.D., George G. Rhoads, M.D., M.P.H., University of Medicine and Dentistry of New Jersey/School of Public Health (8 February 2005)
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Hypokalemia-induced arrhythmia – the assassin in beta 2 agonist treated patients?
- Henning Bundgaard, Marianne Skov, Senior registrar, Ph.D, Department of Pediatrics, Glostrup University Hospital, Copenhagen, Denmark (27 March 2005)
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Gareth I Lloyd, science journalist UK
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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 |
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Christos S Zipitis, SHO Paediatrics St. Mary's Hospital, Whitworth Park, Manchester, M13 0JH, Mark A. Turner
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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 |
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Alistair C Lindsay, SpR Cardiology Barnet General Hospital, Barnet, Hertfordshire, EN5 3DJ. UK, Ameet Bakhai Consultant Cardiologist
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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 |
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George Strube, Retired GP Home. RH11 8AX
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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 |
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Gareth Lloyd, Science journalist UK
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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 |
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Daniel K C Lee, MB, BCh, MRCP, MD Department of Respiratory Medicine, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, Suffolk, England
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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 |
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David Lewis, GP Principal Watford WD24 7PH
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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 |
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Mihai S. Jalba, M.D., Ph.D., postdoctoral research fellow University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, George G. Rhoads, M.D., M.P.H., University of Medicine and Dentistry of New Jersey/School of Public Health
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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.
Competing interests: None declared |
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Henning Bundgaard, Consultant, Ph.D. Medical Department B, The Heart Centre, National University Hospital, 2100 Copenhagen, Denmark, Marianne Skov, Senior registrar, Ph.D, Department of Pediatrics, Glostrup University Hospital, Copenhagen, Denmark
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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 |
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