© 2008 American Thoracic Society doi: 10.1164/rccm.200806-963ED
β-Blockers Are Safe in Patients with Chronic Obstructive Pulmonary Disease, But Only with Caution
University of Rome "Tor Vergata"
Second University of Naples Despite clear evidence of the effectiveness of β-blockers in the management of patients with cardiac disease (heart failure and coronary artery disease) or arterial hypertension, use of these agents has traditionally been contraindicated in chronic obstructive pulmonary disease (COPD) mainly because of anecdotal evidence and case reports citing acute bronchospasm after their administration (1). In particular, it has been reported that selective or nonselective β-blockers increase airway hyperresponsiveness (AHR) (2), a real problem considering that AHR is associated with augmented mortality in patients suffering from COPD (3). The concern of inducing bronchospasm is a likely explanation of the fact that physicians appear to underprescribe β-blockers when patients with cardiac disease are also suffering from COPD (4). The diminished use of β-blockers in patients with COPD is of concern considering that many patients with COPD ultimately die of cardiovascular causes, and from ischemic heart disease in particular (5). Impaired lung function seems to be an independent risk factor for arrhythmias, coronary events, and all-cause mortality and a specific predictor of mortality resulting from cardiac causes (6). The cumulative evidence from trials and meta-analyses indicates that "cardioselective" β1-blockers (exemplified by metoprolol and atenolol) should not be routinely withheld from patients with COPD because the benefits of selective β1-blockers in patients with COPD who also have cardiac disease far outweigh the risks (7). In this issue of the Journal (pp. 695–700), van Gestel and coworkers (8) reinforce this view by providing solid proof that, in carefully selected patients with COPD undergoing vascular surgery, cardioselective β-blockers are safe and indeed beneficial in prolonging survival. This finding indicates that at least β1-blockers are well tolerated in patients with COPD. Although the information from van Gestel and colleagues' study is reassuring, we cannot forget recent analyses that examined the affinity of a wide range of cardioselective β-blockers to a homogenous population of human β-adrenoceptor (AR) subtypes expressed in cell lines, which showed a more limited preference for β1-AR than previously thought, suggesting that many cardioselective β-blockers are blocking β2-ARs in bronchi in addition to blocking β1-ARs in the heart (8). This finding could explain why the effects of the cardioselective β-blocker metoprolol on AHR are the same as those of the nonselective β-blocker propranolol in patients with COPD (2). In a murine model of antigen-induced airway inflammation and AHR, duration of therapy was the determinant of response to β-AR ligands (9). That is, acute treatment with β-blockers increased AHR, whereas chronic treatment (28 d) significantly decreased AHR (10). The mechanism of this phenomenon has not been established but has been suggested to be associated with an increase in β-AR density (10). This intriguing experimental finding was also confirmed in humans. In fact, a small open-label pilot study documented that dose-escalating administration of nadolol, a nonselective β-blocker (with β2-AR inverse agonist properties) that is currently contraindicated in patients with asthma, may be well tolerated and may have a beneficial effect for most subjects with mild asthma when administered chronically (11). Traditionally, the treatment of COPD is based on the use of long-acting bronchodilators, in particular β2-agonists, but there is accumulating evidence showing that β2-agonist use leads to an increased risk for adverse cardiovascular events in patients with COPD (12). It is possible that the antagonist effects of β-blockers may neutralize the actions of β-agonists, so that the risk of adverse cardiovascular events associated with β-agonists may be different in subjects already using β-blockers than among nonusers of β-blockers. However, if it is true that the use of β-blockers leads to an increase in the density of β-ARs, this effect might suggest an increased risk associated with the concomitant use of β-agonists and β-blockers in COPD. Apparently, cardioselective β-blockers not only do not produce increased respiratory symptoms in patients with COPD but they are also associated with an augmented bronchodilator response to subsequent β-agonists (13). This is a clear indication of facilitated β-AR stimulation. However, facilitated β-AR stimulation would also increase heart rate and myocardial oxygen demand (14). Case-control studies have demonstrated an association between β2-agonist use and an increased risk for myocardial infarction, congestive heart failure, cardiac arrest, and acute cardiac death. Intriguingly, the absence of a concurrent possible protective effect of β-blockers has been reported in this situation (15). If the above considerations lead to fear of the unconditional use of β-blockers in COPD, one should also consider a pharmacologic phenomenon that is opposite of what we have just described. In effect, exposure to β-agonists may alter β-ARs such that the affinity for ligands is reduced 10-fold (16). Consequently, prior exposure to β-agonists may reduce binding of antagonists to β2-ARs. This relationship may explain the high tolerance for β-blockers in patients with COPD, who routinely inhale β2-agonists, reported not only by van Gestel and coworkers (8) but also observed in trials and meta-analyses (7). The data therefore are reassuring and indicate that it is possible to use β-blockers in all patients with COPD who need them for concurrent diseases. However, the pharmacologic relationships that we have described come from studies that generally included few patients. In addition, there are currently no prospective long-term data on the safety of β-blockers in COPD. Therefore, although β-blockers can be introduced in any medical setting, it still seems appropriate to use cardioselective β-blockers in patients with COPD at the lowest dose and to titrate slowly with attention to lung function and symptoms (1). FOOTNOTES
Conflict of Interest Statement: M.C. has participated as a speaker in scientific meetings or courses organized and financed by various pharmaceutical companies (Boehringer Ingelheim, GlaxoSmithKline, Sigma-Tau, Recordati); served on an advisory board for Dey (2006, $3,000; 2007, $3,000), Novartis (2007, REFERENCES
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