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CAT CLINIC

Charles DiMaggio, PA-C, MPH
DEPARTMENT EDITOR

Critically appraised topics

Are cardioselective ß-blockers safe to use perioperatively in patients with COPD?

Zachary Hartsell, PA-C; Adriane I. Budavari, MD

Mr. Hartsell practices at the Mayo Clinic Hospital Department of Hospital Internal Medicine. Dr. Budavari is Senior Associate Consultant, Mayo Clinic Hospital Department of Hospital Internal Medicine, and Assistant Professor, Mayo Medical School, Phoenix, Ariz. The authors have indicated no relationships to disclose relating to the content of this article. Dr. DiMaggio is Director, Program for Healthcare Systems Preparedness, National Center for Disaster Preparedness, Columbia University Mailman School of Public Health, New York, NY, and a member of the editorial board of JAAPA.

A 75-year-old man is scheduled to undergo surgical repair for a hip fracture the next day, and you are asked to perform a preoperative cardiovascular risk assessment. The patient's medical history is significant for former tobacco abuse, chronic obstructive pulmonary disease (COPD), type 2 diabetes, hypertension, and hyperlipidemia, which are all well controlled. He has no history of coronary artery disease. His only medications are baby aspirin, hydrochlorothiazide, simvastatin, and an albuterol/ipratropium inhaler. He has dyspnea with moderate exertion on his daily 2-mile walk but no chest pain.

The physical exam reveals a man in pain from a hip fracture; his pulse is 94 beats per minute, and his BP is 160/70 mm Hg. A slightly prolonged expiratory phase is noted on the cardiopulmonary exam, but there is no wheezing or crackles. Laboratory testing indicates only mild renal insufficiency (creatinine 1.8 mg/dL). A chest radiograph demonstrates hyperinflation but no infiltrate; the ECG shows sinus tachycardia with nonspecific ST-T wave changes but no acute ischemic changes.

Using the American College of Cardiology/American Heart Association (ACC/AHA) perioperative cardiovascular evaluation guidelines,¹ you decide that the patient's risk for cardiovascular complications during surgery is low and that he does not need invasive cardiac testing. Although this patient could benefit from perioperative use of a cardioselective ß-blocker to reduce the risk of a cardiac event,²the surgeon is concerned about initiating such therapy in a patient with known COPD because of the risk of inducing bronchospasm.

Clinical question

Can perioperative cardioselective ß-blockers be used safely in patients who have COPD? To answer this question you conduct a literature search of PubMed using the Clinical Queries service and Therapy and Specificity filters, entering the terms beta-blockers and COPD. This search yields 11 articles, one of which is a systematic review of your topic:

Salpeter S, Ormiston T, Salpeter E, et al. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2004;(2).

Further searching of MEDLINE, evidence-based medicine prefiltered databases such as DARE, the Cochrane databases, Clinical Evidence, Best Evidence, Bandolier, and PIER yield no articles that are more pertinent to the question or offer a higher level of evidence.

Evaluating the evidence

The Salpeter paper is a systematic review that examines the effects of cardioselective ß₁-blockers on the respiratory function of patients with COPD (how treatment with ß-blockers affects respiratory symptoms, forced expiratory volume in 1 second [FEV₁], and response to ß₂-agonists). The researchers identified those clinical trials published in any language from 1966 to May 2001 by searching MEDLINE, EMBASE/Excerpta Medica, and CINAHL as well as by scanning symposia abstracts, references of identified studies, and reviews. The systematic review included only randomized, controlled, blinded trials that assessed the effects of a single dose or longer-duration IV or oral cardioselective ß-blockers on symptoms or airway function (FEV₁ at rest at baseline and follow-up) in patients with COPD (baseline FEV₁ less than 80% predicted or as defined by the American Thoracic Society guidelines).

Nineteen crossover trials met these inclusion criteria (n = 267), and 17 of these trials (n = 226) included a placebo-control group. Eleven trials assessed single-dose ß-blocker treatments, and eight trials studied the effects of longer-duration (multiple-dose) treatment ranging from 2 days to 12 weeks. Two investigators independently extracted data. The ß-blockers studied were atenolol, metoprolol, bisoprolol, practolol, celiprolol, and acebutolol.

After analyzing trials that enrolled a total of fewer than 300 patients (almost 80% of whom were male), the Salpeter systematic review concluded that cardioselective ß-blockers did not reduce respiratory function in patients with COPD and did not reduce FEV₁ response to ß₂-agonists. Cardioselective ß-blockers produced no significant change in FEV₁ or respiratory symptoms compared to placebo, given as a single dose (weight mean difference [WMD], –2.05% [95% confidence interval (CI), –6.05% to 1.96%]) or for longer duration (WMD, –2.55% [95% CI, –5.94% to 0.84%]), and did not significantly affect the FEV₁ treatment response to ß₂-agonists. Exacerbations and hospitalizations were recorded in all trials, but none occurred during the periods of study in either group. Furthermore, a subgroup analysis revealed no significant change in results for those participants with severe COPD (FEV₁ less than 1.4 L or less than 50% predicted) or for those with a reversible obstructive component (FEV₁ increase of more than 15% in response to a ß₂-agonist).

While the Salpeter systematic review appears to support the safety of cardioselective ß-blockers in patients with COPD, several factors should be considered. First, as with any analysis of exclusively published trials, the Salpeter review is subject to publication bias. Furthermore, most of the studies are small, which not only underscores the dearth of randomized control trial data on the use of ß-blockers in patients with COPD, but also raises the possibility of a type 2 statistical error (small sample size compromising the statistical power to detect a difference). In addition, the randomization process was not well delineated in many of the studies, some trials were single blinded rather than double blinded, and a few studies lacked placebo controls. Studies in this meta-analysis tended to use therapeutic to supratherapeutic doses; and although the results consistently favored the control groups by a small amount, that difference did not meet statistical significance (perhaps due to the small size of the trials). Finally, because neither this systematic review nor any other studies to date have shown the long-term safety of ß-blockers in COPD, it is possible that larger trials using a longer study period may be required to detect clinically important side effects of ß-blockers in COPD patients.

Clinical bottom line

The data from the Salpeter review suggest that a cardioselective ß-blocker can be considered for patients with stable COPD as it would be for patients without chronic lung disease. ß-blockers have been shown to reduce morbidity and mortality in patients with acute myocardial infarction (MI)³ and hypertension,⁴ to reduce perioperative cardiac events,² and to be beneficial in the treatment of heart failure.⁵ß-blockers are, however, underutilized.⁶ The current standard of care is to avoid these agents in reactive or obstructive airway disease⁷ because COPD has long been considered a contraindication to ß-blocker therapy. After an acute MI, most patients with COPD who are using ß-blocker therapy have a mortality reduction that is equivalent to patients without COPD.⁸ In addition, cardioselective ß-blockers are at least 20 times more potent at blocking ß₁ receptors than ß₂ receptors, conferring less risk of inducing bronchospasm compared with nonselective ß-blockers.⁹

However, because of the potential shortcomings described above, this meta-analysis adds only incrementally to our existing clinical knowledge. Reassuringly, its results are in accord with those of a large study that found no increase in hospital admissions for COPD exacerbations with ß-blocker therapy.⁸

While caution should be used when prescribing ß-blockers in patients with COPD, the above studies demonstrate their relative safety. Careful monitoring after drug administration is prudent. Unexplained respiratory deterioration shortly after starting a ß-blocker warrants discontinuation, and any unexplained exacerbations thereafter should prompt reevaluation of therapy.

REFERENCES

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2. Auerbach AD, Goldman L. beta-Blockers and reduction of cardiac events in noncardiac surgery: scientific review. JAMA. 2002;287:1435-1444.

3. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335-371.

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5. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349-1355.

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7. Murray JF, Nadel JA, Mason RJ, Boushey HA Jr, eds. Textbook of Respiratory Medicine. 3rd ed. Philadelphia, Pa: WB Saunders; 2000:290.

8. Chen J, Radford MJ, Wang Y, et al. Effectiveness of beta-blocker therapy after acute myocardial infarction in elderly patients with chronic obstructive pulmonary disease or asthma. J Am Coll Cardiol. 2001;37:1950-1956.

9. Wellstein A, Palm D, Belz GG, et al. Reduction of exercise tachycardia in man after propranolol, atenolol and bisoprolol in comparison to beta-adrenoceptor occupancy. Eur Heart J. 1987;8(suppl M):3-8.