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Martin et al 1 suggest that caution should be exercised when prescribing long acting oral β agonists to patients at risk of cardiac failure, based on results from a prescription event monitoring (PEM) study.
Firstly, all β2 agonists (short and long acting, oral and inhaled) should be used with caution in patients with severe cardiovascular disease, as is pointed out in the package insert for all drugs of this class.
Secondly, the study does not provide any evidence on this issue. PEM studies are not designed to study causal relations but to generate new hypotheses. Although the authors have made an attempt to consider several potential biases in the analyses, the study design is inappropriate compared with, for example, a prospective randomised controlled trial, and the results must be interpreted with great caution.
Thirdly, no support for an association between bambuterol and an increased risk for cardiac failure has been found in our review of preclinical studies, clinical studies (including >3000 patients/healthy volunteers), or post-marketing surveillance (based on >130 million treatment days).
Fourthly, according to the authors there have been no spontaneous reports of cardiac failure with bambuterol to the Committee on Safety of Medicines. This is in agreement with the WHO database Intdis, with no reports of cardiac failure for bambuterol.
Finally, the paper suggests a doubled asthma mortality in patients receiving salmeterol. In our opinion the reported higher relative risk for non-fatal cardiac failure for bambuterol and the doubled asthma mortality for salmeterol both appear equally explicable by factors other than direct causality, such as confounding by concomitant diseases and disease severity.
Thus, PEM data may be of help in identifying signals with new drugs, but there is little if any merit in comparing drugs used in different populations and introduced to the market at different times.
authors’ reply Bertil Lindmark of Astra Draco makes five points about our study on the risk of non-fatal cardiac failure and ischaemic heart disease with long acting β2agonists. Firstly, he points out that all β2 agonists should be used with caution in patients with severe cardiovascular disease. The cardiac effects of β2 agonists are well described,1-1 but there is limited evidence available on whether or not the risks of adverse cardiac effects differ depending on the dose and method of administration of the drug. Clearly, these are important questions for prescribing doctors faced with treating asthmatic patients with concomitant cardiac disease. An observational cohort study formed from health insurance databases from the Province of Saskatchewan, Canada found an increased relative risk of death from cardiovascular disease in users of β2 agonists taken orally or by nebuliser, but not in users of β2 agonists administered by metered dose inhaler.1-2 The deaths occurred in patients with significant cardiac disease, suggesting that β2 agonists taken orally or by nebuliser should be avoided in patients at high risk of cardiovascular events. We found that the oral β2 agonist bambuterol, but not the inhaled β2 agonist salmeterol, was associated with an increased risk of non-fatal cardiac failure. The results from both these studies are plausible as oral β agonists provide a greater systemic dose than that achieved with metered dose inhalers1-1 and tachycardia and prolonged Q-T interval have been reported principally with nebulised or oral β agonists.1-2 The advised total daily dose of oral bambuterol (20 mg) is 200 times that of inhaled salmeterol (100 μg).1-3
Secondly, Dr Lindmark reiterates our point that the results must be interpreted with caution because the study was observational, and more definitive evidence would come from a prospective randomised trial. Nevertheless, hypotheses about drug safety concerns are often generated from observational studies.1-4 Such studies drive further research because they provide an “a priori” hypothesis and allow the formulation of a clinically relevant end point. Until results from prospective trials become available, observational research using cohort or case-control techniques remains an important source of evidence about the safety of drugs.
Thirdly, he states that a review by Astra Draco has found no evidence from pre-marketing or post-marketing studies of an association between bambuterol and cardiac failure. In general, pre-marketing studies have their own limitations,1-5 as evidenced by the recent withdrawal on safety grounds of two newly launched drugs.1-6Similarly, different types of post-marketing surveillance studies, including PEM, have different advantages and disadvantages and, in general, one system cannot be relied upon to provide all the evidence needed.1-7 This point also applies in response to the fourth comment. In particular, it should be noted that there is gross under-reporting of suspected adverse drug reactions to the Committee on Safety of Medicines1-8 and other regulatory authorities, and there are many difficulties associated with interpreting data from spontaneous reporting schemes.1-5
Finally, as is stated clearly in our paper, it is possible that the association may be explained by factors such as confounding by concomitant disease and disease severity. Interestingly, the rate of cardiac failure associated with bambuterol in the first month of treatment was higher than for 11 cardiovascular drugs previously studied by PEM (table 1-1). Only two cardiac drugs, including the inotropic sympathomimetic xamoterol (licensed for use in mild heart failure) had higher rates of cardiac failure. Since it is highly unlikely that the rate of cardiovascular disease in the bambuterol cohort was higher than in cohorts of patients taking cardiac drugs, and the bambuterol cohort was the youngest, these data provide further evidence that an association cannot be discounted. Our findings require confirmation, but we remain concerned about the size and biological plausibility of the association.
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