Long-acting Beta-agonists in the Management of COPD

Clinical Safety

There is clear consensus with regard to the central role of inhaled bronchodilators as the standard of care in COPD patients. However, recent concerns have been raised suggesting that LABA use could lead to an increased risk of respiratory death in patients with asthma. This was initiated by the results of the Salmeterol Multicenter Asthma Research Trial (SMART), which investigated the safety of adding salmeterol to usual asthma treatment in patients not already receiving a LABA; it was stopped following an interim analysis in 26,355 patients because of a small but significant increase in the number of asthma-related deaths in the salmeterol group. These results raised significant doubts about the safety of LABA monotherapy in patients with asthma. Recent editorials have recommended that physicians should continue to use LABAs to treat asthma, but only when combined with appropriate doses of inhaled corticosteroids.

In COPD there are no restrictions on LABA use as monotherapy. COPD is a distinct disease from asthma, although there is some degree of overlap, with an estimated 10–50% of COPD patients having concomitant asthma. This wide variation in reported prevalence may relate to differences in diagnostic criteria. An overlap in symptoms, together with the lack of validated discriminatory biomarkers, can make differential diagnosis difficult. The major distinguishing features between the two diseases are clinical: in general, COPD occurs later in life, with slowly progressive symptoms during exercise and is associated with a history of smoking or exposure to noxious gases and particulates. Asthma is likely to present early in life (often in childhood) and be associated with symptoms which vary from day to day, often at night or in the early morning; subjects often have a history of asthma in their family and airflow limitation tends to be more reversible than in COPD. It is important to recognize that COPD, in most cases, is associated with significant, albeit never complete, reversibility at one time or another. Therefore, it is not appropriate as is sometimes done, to refer to COPD patients who exhibit significant reversibility in response to a bronchodilator as having an 'asthmatic' component or 'mixed disease'. Indeed, the fact that most COPD patients respond significantly to a bronchodilator provides the major rationale for the recommendation of bronchodilators as the mainstay of therapy for COPD.

LABA monotherapy in COPD is not associated with increased risk of respiratory mortality. A meta-analysis performed in 2006, suggested that β₂-agonists were associated with an increased rate of respiratory deaths compared with placebo, and a 2-fold greater risk of severe exacerbations compared with muscarinic antagonists. However, this meta-analysis did not include the large dataset provided by the TORCH study. TORCH found no increased risk of mortality with salmeterol monotherapy. Indeed, factorial analyses have suggested the numerical mortality benefit observed with the combination (17.5% reduction in risk of death, p = 0.052) might be driven by the LABA component (Table 3). Further, a recent meta-analysis of 27 studies found no significant difference between LABA and placebo in terms of risk of respiratory death (relative risk 1.09 [95%, CI 0.45–2.64]). These results were confirmed in a more recent meta-analysis of 23 trials that also failed to find any increased mortality risk comparing a LABA with placebo (odds ratio 0.95 [95% CI, 0.71– 1.27]).

Clinical studies have demonstrated that both formoterol and salmeterol are well tolerated, over periods of at least a year. Commonly occurring LABA class effects include palpitations, headache and tremor, which may limit the dose that can be tolerated, especially in some older patients. Cardiovascular side effects are also possible in susceptible patients, and there is some risk associated with the use of β₂-agonists in patients with COPD and concomitant cardiac diseases, particularly chronic heart failure.

Chronic heart failure is a frequent comorbidity in patients with COPD. Cazzola et al reported that COPD patients in Italy were at increased risk of chronic heart failure compared with the general population (7.9% compared with 2%), while in a Scottish study, 11.9% patients with COPD also had chronic heart failure. Older individuals were at even higher risk in both studies. Moreover, heart failure may be under-diagnosed in COPD due to diagnostic confusion between the two diseases. Research by Au et al. indicates a strong trend towards a dose-response relationship of increased hospitalization and death, due to heart failure in patients with underlying heart failure who received increasing amounts of β ₂-agonist. Thus it is important that physicians should exercise caution in using high doses of β ₂-agonists in such patients.

However, studies specifically investigating safety have demonstrated that formoterol and salmeterol have good cardiovascular safety profiles. Further, studies with formoterol found a similar profile irrespective of device or formulation. In a large cohort of patients with no or stable cardiac comorbidities, the proportion of patients with treatment-emergent atrial tachycardia ranged from 27%–32% and was nonsignificantly higher, by 2%–5% (p = 0.70), in patients receiving salmeterol or arformoterol compared with placebo; more serious arrhythmias did not increase, nor did mean heart rate.