Class Act: Are beta-blockers really contraindicated for patients with a diagnosis of reactive airway disease?

March 21, 2008

lung.jpgCommentary by Katherine Khvilivitzky, NYU Medical Student

Class act is a feature of Clinical Correlations written by NYU 3rd and 4th year medical students. These posts focus on evidenced based answers to clinical questions related to patients seen by our students in the clinics or on the wards. Prior to publication, each commentary is thoroughly reviewed for content by a faculty member.

In the past, reactive airway disease was considered to be a contraindication to administration of all beta-blockers including ophthalmic preparations. Concern had been raised by case reports of acute bronchospasm, at times leading to death, with non-cardioselective beta-blocker administration. (1,2) This occurs because a blockade of beta-2 receptors on bronchial smooth muscle cells leads to impaired airway dilation in response to adrenergic stimulation. In fact, older guidelines listed asthma as an absolute contraindication to administration of non-cardio-selective beta blockers including eye drops used in glaucoma treatment.(3) However, currently there are several cardioselective agents such as atenolol, bisoprolol, and metoprolol that are at least 20 times more potent at blocking beta-1 receptors than beta-2 receptors.(4)

Beta-receptor blockers have been shown to reduce mortality in patients with hypertension, heart failure, and coronary artery disease. (5,6) They are also useful in the management of arrhythmias, thyrotoxicosis, and to reduce complications in the peri-operative period.(7,8,9) Despite the overwhelming evidence for these benefits, beta blockers are underutilized in clinical practice. Nationwide prescribing patterns showed that, of all patients discharged after surviving a myocardial infarction, only 40% were prescribed beta-blockers.(10) Chronic obstructive pulmonary disease (COPD) and asthma were the co-morbidities most commonly cited as the reason for withholding beta-blockers after a myocardial infarction.(6)

A 2002 Cochrane Review analyzed 29 randomized, blinded, placebo-controlled trials assessing the risk of administering cardioselective beta-blockers to patients with reversible airway disease. (11) These studies included subjects between 19 and 65 years of age with asthma or COPD with a known reversible component. The interventions consisted of oral or parenteral cardio-selective beta-blocker or placebo administered either as a single dose or as continued treatment ranging from 3 days to 4 weeks. Outcome measures included change in forced expiratory volume in 1 second (FEV-1), and symptoms such as dyspnea or wheezing. Also, after administration of placebo/beta-blockers, some patients went on to receive a beta-2-agonist. The degree of FEV-1-change in response to the bronchodilators was measured to look for any impact of beta-blockade on the effectiveness of the asthma medications. Change in weekly use of short-acting beta-2-agonists was also monitored for the continued-treatment patients.

The analysis found that with administration of the first dose of a beta-1-blocker there was a small (7.46% [95%CI, 5.59 to 9.32%]) asymptomatic decrease in FEV-1. After continued treatment for several days to weeks, there was no difference between the beta-1-blocker and placebo groups in FEV-1 (-0.42% [95%CI, -3.74 to 2.91%]) or inhaler use (-0.11% [95%CI, -6.75 to 6.54%]). In fact, no trial demonstrated any symptoms in response to administration of cardioselective beta blockers. Interestingly, compared with placebo, the treatment groups had an increased degree of positive FEV-1-response to beta-2-agonists after single (4.63% [95%CI, 2.47 to 6.78%]) or continued beta-blocker (8.74% [95%CI, 1.96 to 15.52%]) treatment. The review discusses how this could be due to upregulation and/or sensitization of beta-2-receptors or increased endogenous stimulation of all adrenergic receptor types after consistent exposure to the beta-1-blocking agents.
The authors concluded that, when beta blockers are indicated, they should not be withheld from patients with mild to moderate reversible airway disease due to concern about pulmonary symptom exacerbations. It should be noted, however, that most of the participants were relatively young with an average age of 40. This is younger than most patients who require a beta-blocking agent for management of coronary artery disease.(12) Also, those with recent asthma exacerbations were often excluded from the trials but no quantitative cut-off was given for the statement. Most of the studies followed patients for relatively short treatment durations of days to weeks and it is unclear if there would have been a long-term increase in symptoms, inhaler use or exacerbations. More investigation would be needed to understand the effects of long-term beta-blocker use on frequency of exacerbations, hospitalizations and death rates. The report recommended starting with low daily doses of cardioselective beta-1-blockers and titrating up while monitoring any changes in symptoms, inhaler use and frequency of acute exacerbations.

There was some concern raised in response to the review regarding generalizing the results to patients with higher severity of disease. The slight decrease in FEV-1 that was well-tolerated by the subjects in the studies may overwhelm the reserve of a patient with greater underlying bronchospam. The resistance to airflow increases exponentially as the radius of an airway decreases, meaning that a small change in luminal size related to inflammation and increased secretion can greatly affect the work of breathing in the setting of a serious asthmatic attack.(13)

The 2007 NIH guidelines for asthma management state that, if indicated for management of vascular disorders, cardioselective beta-blockers may be administered after careful evaluation.(14) The Expert Panel Report 3 put forth the NIH recommendations and cited the findings of the Cochrane database review as evidence to suggest that patients with mild-moderate airway obstruction can tolerate these agents. The American College of Cardiology/American Heart Association Guidelines revised in 2004 state that although asthma was once thought to preclude the use of beta blockers in some patients, current evidence suggests that the benefits may actually outweigh the risks in patients with mild asthma not currently active.(15) The guidelines recommend close follow-up and caution to select only cardio-selective beta-blockers for these patients.

The results of previous trials presented in the Cochrane review and the subsequent acceptance of the data by the NIH Expert Panel to be included in the new Guidelines lead to the conclusion that beta-1-blockers should not be automatically withheld in the setting of known reactive airway disease. Instead, it seems reasonable to base the treatment decision for each individual patient on the severity of asthma balanced with the benefits of morbidity and/or mortality reduction to be gained from beta-blockers. A mild to moderate asthmatic without recent exacerbations can be started on a cardio-selective beta-1-blocker in the presence of diagnosed cardiovascular disease that is an indication for this treatment. Based on evidence, the cardio-selective beta-1-blockers should not increase inhaler use or symptoms when used on a continued plan. In fact, continued treatment may increase sensitivity to the beta-2-agonist agents that are used in asthma treatment. I would be careful in generalizing these results to very old patients, patients with severe asthma, or those with a recent exacerbation requiring hospitalization, intubation, or any other indicator of great severity of airway disease.

References:

 

  1. Kendall MJ. Clinical Relevance of Pharmacokinetic Differences between Beta-Blockers. Am J Cardiol. 1997;80:15J-19J

  2. Tatterfield AE. Beta Receptor Antagonists and Respiratory Disease. J Cardiovasc Pharmacol. 1986;8 Suppl 4:S35-9.

  3. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma. Bethesda, National Institute of Health, 1997, NIH Publ No. 97-4051.

  4. Wellstein A, Palm D, Belz GG, Butzer R, Polsak R, Pett B. Reduction of exercise tachycardia in a man after propranolol, atenolol, and bisoprolol in comparison to beta-adrenoreceptor occupancy. Eur Heart J. 1987;8 Suppl M:3-8.

  5. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta Blockade after Myocardial Infarction: Systematic Review and Meta Regression Analysis. BMJ. 1999;318:1730-7.

  6. Chafin CC, Soberman JE, Dernirkan K, Self T. Beta Blockers After Myocardial Infarction: Do Benefits Ever Outweigh Risks in Asthma. Cardiology. 1999;92:99-105

  7. Klein I, Becker DV, Levey GS. Treatment of Hyperthyroid Disease. Ann Intern Med. 1994;121:281-8.

  8. Everly MJ, Heaton PC, Cluxton Jr RJ. Beta-Blocker Underuse in Secondary Prevention of Myocardial Infarction. The Annals of Pharmacotherapy. 2004;38:286-293.

  9. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on Mortality and Cardiovascular Morbidity after Non-cardiac Surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. 1996;3351713-20.

  10. Ellerbeck EF, Jencks SF, Radford MJ, Kresowik TF, Craig AS, Gold JA, Krumholz HM, Vogel RA: Quality of Care for Medicare Patients with Acute Myocardial Infarction: A four-state pilot study from the Cooperative Cardiovascular Project. JAMA. 1995;273:1509-1514.

  11. Salpeter S, Ormiston T, Salpeter E, Wood-Baker R. Cardio-selective Beta-Blockers for Reversible Airway Disease. Cochrane Database of Systematic Reviews. 2002, Issue 4.

  12. Epstein PE. Fresh Air and Beta-Blockade [Editorial]. Annals of Internal Medicine. 2002;137:766.

  13. Shulan DJ, Katlan M, Lavsky-Shulan M. Use of Beta-Blockers in Patients with Reactive Airway Disease [Letter to the Editor]. Annals of Internal Medicine. 2003;139:304.

  14. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, National Institute of Health, 2007.

  15. Antman EM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1999 guidelines for the management of Patients with Acute Myocardial Infarction). J Am Coll Cardiol 2004.

Image courtesy of Wikimedia Commons

One Response to Class Act: Are beta-blockers really contraindicated for patients with a diagnosis of reactive airway disease?

  1. stickler on March 25, 2008 at 1:31 pm

    When you say “reactive airway disease” I think you mean airway or bronchial hyper-reactivity. “Reactive airway disease” or “reactive airways dysfunction syndrome” is a specific form of irritant induced asthma that usually results from the sudden inhalation of a large dose of a highly irritating substance.

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