Cardioselective Beta Blocker Use in Patients With Asthma and Chronic Obstructive Pulmonary Disease: An Evidence-Based Approach to Standards of Care

Shelley R. Salpeter, MD

Disclosures

Cardiovasc Rev Rep. 2003;24(11) 

In This Article

Beta Blockers in COPD or Asthma

Many patients with obstructive lung diseases have concomitant conditions such as hypertension, coronary artery disease, or congestive heart failure that necessitate the use of ß blockers. However, review articles and practice guidelines consistently list asthma and COPD as contraindications to ß-blocker use.[16,17] Only a small proportion of patients with cardiac disease who would benefit from ß blockers currently receive this treatment, mainly due to unfounded fears about their adverse effects. Asthma and COPD have been found to be the comorbid conditions most commonly associated with the withholding of ß blockers in patients with myocardial infarction.[18] Now, with the accumulation of data over the past several years, we can clearly track the transition from myth to evidence concerning the use of ß blockers in patients with obstructive airway disease.

The original evidence of a potential adverse effect of ß blockers in asthma and COPD was based on case reports of acute bronchospasm precipitated by high doses of noncardioselective ß blockers.[19,20] Despite an absence of evidence beyond these case reports, the concept that ß blockers caused increased bronchospasm and severe asthma exacerbations became dogma. For that reason clinicians tend to avoid the use of ß blockers in patients with cardiac conditions if there was even a remote history of obstructive airway disease.

The standard of care for the treatment of asthma or COPD, even in the presence of cardiac disease, is the use of ß-2-agonist drugs. Short-term use of ß-2 agonists has been shown to result in improvements in respiratory symptoms through the actions of bronchodilation and protection against bronchoconstrictive stimuli. Subsequently, it has been assumed that the regular use of ß-2 agonists will result in long-term benefits for patients with asthma and COPD.

Evidence Concerning Cardioselective ß Blockers. Over the past 20 years, nonselective ß blockers have largely been replaced with cardioselective blockers. Cardioselective ß blockers such as atenolol and metoprolol are at least 20 times more potent at blocking ß-1 receptors than ß-2 receptors.[1] At therapeutic doses the ß-2 blocking effect, and therefore the risk of bronchoconstriction, is negligible. In addition there is strong evidence that ß blockade causes up-regulation and sensitization of ß receptors, making them more sensitive to endogenous or exogenous adrenergic stimulation.[3,4]

Two meta-analyses have recently been published that address the evidence concerning adverse respiratory effects of cardioselective ß blockers in patients with obstructive lung disease. In one analysis, the effect of cardioselective ß blockers in patients with reactive airway disease was reviewed.[21] Reactive airway disease was defined as asthma or COPD with a reactive component. The study evaluated 29 trials with 381 participants in which treatment was given either as a single dose or for a longer duration lasting 3 days to 4 weeks. The pooled results showed that a single dose of a cardioselective ß blocker caused a small decrease (7%) in the forced expiratory volume at 1 second (FEV1) that was not associated with adverse respiratory symptoms compared with placebo but that caused a 5% increase in FEV1 response to ß-2 agonist (Figures 1 and 2). After continued use for a few days to weeks, the FEV1 incidence of respiratory symptoms and ß-2-agonist inhaler use was not significantly different from placebo (Figure 3). However, a 9% increase in ß-2-agonist response was maintained compared with placebo, supporting the concept of receptor sensitization or up-regulation (Figure 4). A subgroup analysis demonstrated similar results in those participants with comorbid cardiac conditions like hypertension.

Forced expiratory volume at 1 second treatment effects (treatment minus placebo, percent change from baseline) for single-dose studies in patients with reactive airway disease. For agonist inhaler use for those trials that studied two different ßblockers, the study is listed twice. CI=confidence interval

Forced expiratory volume at 1 second treatment effects after ß-2 agonists for singledose studies in patients with reactive airway disease. For those trials that studied two different ßblockers, the study is listed twice.

Forced expiratory volume at 1 second treatment effects for continued treatment studies in patients with reactive airway disease. For those trials that studied two different ßblockers, the study is listed twice.

Forced expiratory volume at 1 second one treatment effect after ß-2 agonists for continuedtreatment studies in patients with reactive airway disease. For those trials that studied two different ß blockers, the trial is listed twice.

Patients with COPD are at greater risk of ischemic heart disease than asthmatics and would benefit from the use of ß blockers. However, they also have more severe airway obstruction so may be more sensitive to small changes in FEV1. A second meta-analysis evaluated ß-blocker use in patients with documented COPD.[22] Nineteen trials with 267 participants were included. The pooled results showed no change in FEV1, respiratory symptoms, or ß-2 agonist inhaler use for single doses or continued treatment with cardioselective ß blockers compared with placebo (Figure 5). Subgroup analyses revealed no difference in results for those with a reactive airway component or with comorbid cardiovascular conditions such as hypertension or angina. In addition, there was no difference in results for those with severe COPD, as demonstrated by a baseline FEV1 less than 1.4 L or less than 50% the normal predicted value.

Forced expiratory volume at 1 second (FEV1) treatment effects for single-dose and longer-duration trials in patients with chronic obstructive pulmonary disease

It should be noted that of the 97 trials on cardioselective ß-blocker use in obstructive airway disease that were evaluated for inclusion in the two meta-analyses, none demonstrated an increase in respiratory symptoms for ß blockers compared with placebo or baseline values. The doses of cardioselective ß blockers that were used in the trials ranged from therapeutic to mildly supratherapeutic. For example, single-dose studies using atenolol or metoprolol in doses ranging from 50-200 mg showed no adverse effect on respiratory function. No trials used doses high enough to diminish cardioselectivity.

The findings from these meta-analyses are consistent with other studies that have shown that the use of cardioselective ß blockers in patients with COPD and concomitant cardiovascular disease is well tolerated.[15,23,24,25,26,27,28,29] One study on survivors of myocardial infarction included 46,000 patients with concomitant asthma or COPD and showed a significant reduction in total mortality for those treated with ß blockers compared with those who were not.[30] This indicated that when ß blockers are withheld from patients with obstructive airway disease, the mortality benefits associated with these medications are also withheld.

Evidence Concerning Noncardioselective ß Blockers. When ß blockers were first introduced, there were scattered reports of acute bronchospasm precipitated by high doses of noncardioselective blockers, presumably due to their blockade of ß-2 receptors on bronchial smooth muscle.[19,20] To evaluate the effect of nonselective ß blockers on respiratory function in obstructive lung disease, the results of 16 trials that evaluated noncardioselective ß blockers were pooled.[21] Regular use of nonselective ß blockers compared with placebo caused a 14% reduction in FEV1 and a 23% decrease in the FEV1 response after ß-2 agonists were given. No significant increase in respiratory symptoms or ß-2 agonist inhaler use was seen in any of the trials. However, the decrease in ß-2-agonist response seen with nonselective ß blockers may indicate an increased risk for a clinically significant adverse effect during an asthma exacerbation.

One study recently evaluated the tolerability of carvedilol, a noncardioselective ß blocker, in patients with congestive heart failure and concomitant obstructive lung disease.[31] This study was an open-label investigation of 487 participants taking carvedilol, 43 of whom had COPD or asthma. Over the course of 2.4 years, one of the patients with COPD and three of those with asthma discontinued the carvedilol secondary to wheezing. Unfortunately, there was no control group of patients not on carvedilol to compare these results with. Despite being methodologically flawed, this study raises the question of whether nonselective ß blockers like carvedilol are completely safe in patients with congestive heart failure and concomitant obstructive airway disease.

Evidence Concerning ß-2 Agonists. The regular use of inhaled ß-2 agonists is the standard of care in the treatment of asthma and COPD. However, continued use for 1-6 weeks has been shown to result in a significant reduction in the bronchodilator response to subsequent ß-2 agonist as well as a reduction in protection against bronchoconstrictive stimuli compared with placebo.[5,32,33,34,35,36,37] The tolerance to the bronchodilator and nonbronchodilator effects of ß-2 agonists that develops could explain the association that has been found in case-control studies and surveillance safety studies between ß-2 agonists and an increased risk for fatal and near-fatal asthma attacks.[38,39]

For patients with obstructive airway disease and concomitant congestive heart failure or ischemic heart disease it is common practice to give ß-2 agonists while withholding ß blockers. There are now several case-control studies that have documented an association between ß-2 agonist use and the development of congestive heart failure, acute myocardial infarction, or cardiac death.[40,41,42,43] This association may be explained by ß-agonist stimulation causing tachycardia, hypokalemia, and arrhythmia, especially in the presence of cardiac comorbidities or hypoxemia.[44]

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