Beta-blockers have an established role in cardioprotection both in primary and secondary prevention. There is enormous evidence that b-blockers (especially lipophilic) reduce coronary mortality. Furthermore, there is good evidence from recent studies that diabetics, asthmatics, elderly and those with impaired left ventricular function do derive considerable benefit from b-blockade. Yet, studies indicate that b-blockers are vastly underutilized.

‘b Scope', in the current and subsequent issues, attempts to provide the current evidence-based perspective on the use of b-blockers in special patient population. The purpose of this second issue is to evaluate the benefits and risks associated with use of b-blockers in patients of asthma or COPD and to provide treatment recommendations based on evidence.

Introduction

Many patients with reactive airway disease, with or without a chronic obstructive component, have concomitant conditions such as myocardial infarction or cardiac arrhythmias, which necessitate the use of b-blockers. Patients with chronic obstructive pulmonary disease (COPD) are thought to be at a greater risk than those with reactive airway disease for developing ischemic heart disease and other cardiovascular conditions requiring the use of b-blockers.1

Yet, physicians have persistently resisted the use of b-blockers in patients with acute or chronic obstructive lung disease, and many people who might otherwise have survived as a result of b-blocker use have probably died because they were not given these agents.

A study2 showed that COPD and asthma were the co-morbid conditions most commonly associated with b-blockers being withheld in elderly patients after a myocardial infarction. The reason for this paradox is that a number of publications have implicated b-blockers as the causative agent in fatal exacerbations of broncho- spasm.2 Review articles usually list asthma and COPD as contraindications to b-blocker use, citing cases of acute bronchospasm during administration of noncardioselective b-blockers.1

 

Clinical Experiences

 

Dramatic descriptions of death and disaster have mostly appeared as case reports and have largely involved non-selective b-blockers that are much more likely than cardioselective agents to affect bronchial tone.2 Based on an understanding of b- adrenergic receptor antagonism, a cardioselective b-adrenergic receptor blocker would be expected to have an advantage over a non-selective blocker in patients with asthma.

Cardioselective b-blockers, or b1- blockers such as atenolol, bisoprolol, and metoprolol, have greater than 20 times more affinity for b1-receptors than for b2-receptors and in theory should pose much less risk for bronchoconstriction and at therapeutic doses, their b2-blocking effect is negligible.1

Several studies have evaluated the differential effects of a cardioselective and a non-selective b-adrenergic blocker on parameters of pulmonary function in patients with asthma or COPD, with or without cardiovascular diseases. Atenolol, bisoprolol, celiprolol and metoprolol are the four cardioselective agents used most frequently in the clinical trials.3

Patients with severe asthma, particularly those with active bronchospasm, may react differently to mild b-blockade than patients with stable, relatively inactive asthma. As observed in single-dose trials, there is a mild, clinically insignificant decrease in FEV1 in patients with no (or minimal) narrowing of the bronchi, indicated by the fact that no difference was noted in symptoms between the treatment and the placebo groups. On the other hand, resistance to airflow increases with the fourth power of the radius of the bronchus; hence, in patients with severe underlying bronchospasm, small changes in luminal size will cause major changes in breathing. Therefore, a slight acute effect of b-blockade in patients with severe asthma may produce a cascade of events that results in a serious asthmatic attack.2

The above considerations seem somewhat less important in patients with chronic obstructive pulmonary disease than in patients with asthma, since bronchospasm is much less common and usually less severe in the COPD group. Acute exacerbations of COPD are more often related to mucus obstruction of the bronchi than to acute narrowing of their anatomic structure.2 The stimuli to hyperresponsiveness in patients with COPD may be different from those in patients with asthma, and b-blockade may not cause bronchoconstriction in patients with COPD.4

EVALUATING EFFECT OF BETA-BLOCKERS ON BRONCHIAL RESPONSE IN ASTHMATICS

 

a. Placebo-controlled studies

Early trials with propranolol revealed that patients with asthma frequently experienced bronchospasm, which could be severe. In a clinical trial5, it was reported that intravenous propranolol 0.1 mg/kg resulted in a mean 9% decrease in FEV1 in patients with very mild asthma. It also mentioned that two subjects with moderately severe asthma had prolonged and severe bronchospasm associated with propranolol administration. Subsequent trials verified that non-specific b-blockers should be avoided in patients with asthma.5

A double-blind comparative trial between metoprolol and placebo examined the effect of a single oral dose of metoprolol 40 mg on the bronchial response to isoproterenol aerosol in 24 asthmatic patients. No subject had experienced an asthma attack during the previous 3 weeks. Ninety minutes after administration of metoprolol or placebo, vital capacity (VC) and forced expiratory volume in 1 second (FEV1) were measured. The patients then inhaled 0.4 mg of an isoproterenol aerosol, and VC and FEV1 were measured. The VC and FEV1 were 3.98±1.02 and 2.94±0.76, respectively, before and 3.97±1.01 and 3.19 ± 0.78 after metoprolol administration (Figure 1).

No significant difference was seen between metoprolol and placebo groups in bronchial response to isoproterenol aerosol.6

 

b. Beta-blocker comparison studies

The effects of a single oral dose of propranolol 80 mg were compared with those of metoprolol 100 mg on specific airway resistance (Sraw = a product of airway resistance and thoracic gas volume) in 6 healthy subjects and 12 patients with a 5-year or longer history of bronchial asthma requiring long-term treatment with bronchodilators but not corticosteroids. Both propranolol and metoprolol produced an increase in Sraw in patients from control levels (baseline), but the differences were significant only for propranolol.6

The study concluded that propranolol significantly impairs ventilatory function in asthmatics which is not observed with metoprolol.6

In another study, the effects of intravenous propranolol 0.06 mg/kg, intravenous metoprolol 0.12 mg/kg, and placebo on pulmonary function were compared in seven asthmatic patients. Both b-blockers reduced basal FEV1, but the effect was more pronounced after propranolol.

Metoprolol did not significantly inhibit the effect of isoprenaline on FEV1 except at the lowest dosages of isoprenaline, whereas propranolol almost completely inhibited the effect of isoprenaline at all dosages.6

The effects of approximately equipotent single oral doses of three cardioselective b-blockers, atenolol 100 mg, metoprolol 100 mg, and acebutolol 300 mg and four non-cardioselective b-blockers, propranolol 100 mg, oxprenolol 100 mg, pindolol 5 mg, and timolol 10 mg - on heart rate and FEV1 were studied in 10 asthmatic patients, all with reversible airway obstruction. All drugs except pindolol led to a significant reduction in standing heart rate and prevented an increase in heart rate after inhaled isoprenaline. In addition, all drugs caused a fall in FEV1, but only atenolol did not differ significantly from placebo in this respect. The bronchodilator response to inhaled isoprenaline was observed only with the three cardioselective drugs.

These data suggested that no beta-blocker is absolutely safe for asthmatic patients but that cardioselective b-blockers best preserve the bronchodilator action of b-stimulant such as isoprenaline.6 Similarly, other studies have demonstrated that asthmatics requiring b-blocker therapy could be administered low doses of cardioselective agents with minimal adverse effects on pulmonary function.5

 

ASTHMATICS WITH MYOCARDIAL INFARCTION: Benefits outweigh the risks

The Cooperative Cardiovascular Project data was used in a study to determine which patients benefit from the use of beta-blockers.4 In this study, the rate of mortality in 201,752 patients with MI was compared among patients treated with b-blockers and those who were not. Only 34% of patients received b-blockers with the percentage being low among patients considered sickest, including those with pulmonary diseases.

In patients with a history of asthma, risk of death at 2 years was lower in patients receiving b-blockers.

Among 3819 patients with asthma receiving b-blocker therapy (n=676), there was an 11.9% risk of death versus 19.7% risk in those asthmatics not receiving this therapy (n=3,143) (Figure 2).

Also among 41,814 patients with COPD receiving b-blocker therapy (n=9228), there was a 16.8% risk of death versus 27.8% risk in those COPD patients not receiving this therapy (n=32,586) (Figure 3). Mortality was reduced significantly by 40% in both the subgroups.

This data clearly suggest benefits of b-blocker therapy in MI patients with asthma or COPD.

Another study7 evaluated the use and effectiveness of beta-blocker therapy after acute myocardial infarction (AMI) for patients with chronic obstructive pulmonary disease (COPD) or asthma, again using data from the Cooperative Cardiovascular Project. They examined the relationship between discharge use of beta-blockers and one-year mortality in patients with COPD or asthma who were not using beta-agonists, patients with COPD or asthma who were concurrently using beta-agonists and patients with evidence of severe disease (use of prednisone or previous hospitalization for COPD or asthma) compared with patients without COPD or asthma. The results showed that of 54,962 patients without contraindications to beta-blockers, patients with COPD or asthma (20%) were significantly less likely to be prescribed beta-blockers at discharge after AMI.

After adjusting for demographic and clinical factors, it was found that beta-blockers were associated with lower one-year mortality in patients with COPD or asthma who were not on beta-agonist therapy (relative risk [RR] = 0.85), similar to patients without COPD or asthma (RR = 0.86). A survival benefit for beta-blockers was not found among patients concurrently using beta-agonists or with severe COPD or asthma. Hence, it was concluded that beta-blocker therapy after AMI might be beneficial for COPD or asthma patients with mild disease.

 

The ACC/AHA guidelines recommend the following:

 

“Although relative contraindications once may have been thought to preclude the use of b-blockers in some patients, new evidence suggests that the benefits of b-blockers in reducing reinfarctions and mortality may actually outweigh its risks, even in patients with asthma; insulin-dependent diabetes mellitus; chronic obstructive pulmonary disease; severe peripheral vascular disease, PR interval >0.24 s; and moderate LV failure. It is also emphasized that the use of b-blockers in such patients requires careful monitoring of the patient to be certain that adverse events do not occur.”8

 

ASTHMATICS WITH HYPERTENSION

Studies6,9 have shown that patients with reversible airways obstruction who require beta-blockade should be given a low dose of a cardioselective agent in conjunction with, if required, a b2-stimulant such as isoprenaline. Such a treatment will be less likely to cause a troublesome increase in airways resistance and the bronchodilator action of the b2-stimulant will be almost fully preserved.

However, studies evaluating the effect of beta-blockers in hypertensive patients with asthma have involved small numbers of patients over short periods of time. Since a wide range of other classes of antihypertensives are available, b-adrenergic blockers should be generally avoided in patients with a history of asthma. However, if a patient with asthma and hypertension is unable to tolerate other classes of antihypertensive medications, a trial of a cardioselective b-adrenergic blocker could be attempted while maintaining optimal treatment with bronchodilators.3

 

META-ANALYSES: The Consensus

in REACTIVE AIRWAYS DISEASE

A recent meta-analysis1 evaluated the effect of cardioselective b1-blockers on respiratory function in patients with reactive airways disease (defined as asthma or COPD with a reversible component) by collating evidence from randomized, blinded, placebo-controlled trials (19 studies on single-dose treatment and 10 studies on continued treatment).

The main results of the meta-analysis are as follows :

• Administration of a single-dose of a cardioselective beta-blocker was associated with a 7.46% decrease in FEV1 and a 4.63% increase in FEV1 response to beta-agonist compared with placebo, with no increase in respiratory symptoms such as wheezing, dyspnoea or exacerbation of asthma.

• Trials lasting from 3 days to 4 weeks produced no significant change in FEV1, respiratory symptoms, or inhaler use compared with placebo but maintained an 8.74% increase in beta-agonist response.

• No significant treatment effect in terms of FEV1, was found in patients with concomitant obstructive pulmonary disease, irrespective of whether single doses (change in FEV1, 5.28%) or continued treatment (change in FEV1, 1.07%) was given.

• Subgroup analyses were performed to evaluate the effect of cardioselective beta-blockers on patients with concomitant COPD or cardiovascular diseases, such as hypertension, because these patients are most often targeted for beta-blocker treatment. No significant difference in the FEV1 treatment effect or incidence of symptoms or inhaler use was observed.

• The doses of b-blockers that were evaluated ranged from therapeutic to mildly supratherapeutic. For example, single-dose studies using atenolol or metoprolol in doses ranging from 50 to 200 mg showed no clinically apparent effect on respiratory function.

• Of the 80 trials on cardioselective beta-blockers that the meta-analyses had identified, none demonstrated an increase in respiratory symptoms for b1-blockers compared to placebo or baseline values.

This meta-analysis concluded that cardioselective b-blockers, given as a single dose or as continued treatment, were associated with an increase in response to b2-agonists compared with placebo. Cardioselective beta-blockers do not produce clinically significant adverse respiratory side effects in patients with mild to moderate reactive airways disease. Given their demonstrated benefit in such conditions as heart failure, cardiac arrhythmias, and hypertension, cardioselective beta-blockers should not be withheld from patients with mild to moderate reactive airways disease.

 

in CHRONIC OBSTRUCTIVE AIRWAYS DISEASE

Another meta-analysis10 was conducted to assess the effects of cardioselective beta-blockers on respiratory function in patients with COPD. Data was collected from randomized, blinded, controlled trials of single dose (11 studies) or longer duration (8 studies) ranging from 2 days to 12 weeks.

The main results of the meta-analysis are as follows:

• Cardioselective beta-blockers produced no statistically significant change in FEV1 or respiratory symptoms compared to placebo, given as a single dose (weighted mean difference -2.05%) or for longer duration (weighted mean difference -2.55%), and did not significantly affect the FEV1 treatment response to beta2-agonists.

• Exacerbations and hospitalizations were recorded in all trials, but none occurred during the period of study, in either group.

• Subgroup analysis revealed no significant change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component.

The available evidence suggests that cardioselective beta-blockers given to patients with COPD do not produce a significant short-term reduction in airway function or in the incidence of COPD exacerbations.

Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should be considered for patients with COPD, but administered with careful monitoring since data concerning long-term administration and their effects during exacerbations are not available.

The cumulative evidence from these two meta-analyses provides substantial assurance to the clinician that cardioselective b-blockers are safe and that cardioselective b-blocker therapy should be considered in patients with mild to moderate asthma or patients with COPD. These drugs should be initiated at low doses and if tolerated, the dose should then be increased as needed to achieve the desired clinical effect.2

 

OPTIMIZING CURRENT BETA-BLOCKER THERAPY:
Role of metoprolol extended-release

 

The extended-release form of metoprolol, recently introduced in the Indian market offers distinct advantages over the conventional metoprolol formulation and other b-blockers.

• The extended-release metoprolol formulation produces a superior b1-blocking effect at 24 hours and over a period of 24 hours as compared to conventional b-blockers, with lesser plasma fluctuations.11

• Metoprolol extended-release does not achieve high peak plasma concentrations as compared to conventional beta-blockers, hence it has lesser risk of diminished cardioselectivity and hence lesser incidence of b2-mediated side effects like bronchoconstriction and fatigue.11

• In patients with asthma or obstructive airways disease, controlled-release formulations of metoprolol provided equal or greater cardioselectivity than conventional atenolol or long-acting propranolol. In a small group of 8 asthmatic patients, effects associated with b-adrenoceptor antagonism were more pronounced with atenolol than with metoprolol extended-release at comparable therapeutic doses and at a time coinciding with maximum plasma drug concentrations.12 Physiological tests such as ventilatory function and skeletal muscle tremor estimation were performed at baseline and at various times after single dose administration of metoprolol extended-release 100 and 200 mg, atenolol 100 mg and placebo in this double-blind crossover study. Following ingestion of each tablet, the b2-agonist terbutaline was administered in increasing dose by intravenous infusion and inhalation. Measurement of FEV1 after terbutaline infusions and inhalations was 0.39 L lower with atenolol than with metoprolol extended-release 100 mg (p< 0.05) and 0.33 L lower with atenolol than with metoprolol extended-release 200 mg (p < 0.05), indicating a higher degree of b2- blockade with atenolol.

Thus, metoprolol extended-release appears to produce a significantly lesser effect on b2-mediated processes than a conventional formulation of atenolol, and this is attributed to the lack of high plasma peak concentrations, unlike atenolol. Hence it could represent a choice beta-blocker in patients with co-existent asthma or COPD.

 

Conclusion

Beta-blockers have long been withheld from use in hypertension and myocardial infarction patients with concomitant asthma and COPD. However, a review of clinical data reveals greater safety in addition to the established benefits while using cardioselective beta-blockers as compared to non-selective beta-blockers. In asthmatics with hypertension, unable to tolerate other classes of antihypertensive medications, a cardioselective b-blocker could be administered along with optimal treatment with bronchodilators. Importantly, given their demonstrated benefits in MI, these agents should not be withheld from such patients.

 

References :

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2. Ann Intern Med 2002; 137: 766-767
3. Chest 2003; 123: 222-243
4. JACC 2001; 37: 1950-1956
5. NEJM 1998; 339: 489-497
6. Cardiology 1999; 92: 99-105
7. Cochrane Database Syst Rev. 2002; (2): CD003566
8. Circulation 1999; 100: 1016-1030
9. Eur J Clin Pharmacol. 1981; 21: 173-6
10. AHJ 2000; 140: 663-671
11. J Clin Pharmacol 1990; 30: S39-S45
12. Eur J Clin Pharmacol 1988; 33(Suppl): S25-S32