By: Syed Arafath, PharmD Candidate c/o 2015, AMSCOP at LIU

–

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, behind heart disease and cancer.¹ Many patients with COPD often present with multiple-organ dysfunction, especially cardiovascular disease.^2,3 COPD and heart failure frequently coexist in approximately 30% of cases in clinical practice, and COPD by itself can be an independent risk factor for developing cardiovascular disease.^{4, 7} Beta-blockers are found to be beneficial in reducing morbidity and mortality in patients with cardiovascular disease, especially heart failure (HF).⁵ However, patients with COPD are often given a sub-therapeutic dose of a beta-blocker because of the possible effect on airway obstruction, and reduced efficacy of beta₂-agonist and forced expiratory volume in one second (FEV₁).⁶ Therefore, the management of coexistent COPD and HF poses a unique therapeutic challenge.

      Historically, beta-blockers have been avoided and considered contraindicated in patients with COPD.⁷ Furthermore, many beta-blockers have prescribing information that warn against use in COPD patients however, if needed, allows clinicians to consider low doses (Table 1). Recent studies have demonstrated that it is considerably safer to use cardio-selective beta-blockers in COPD patients.^8-9 However, the selectivity of cardio-selective beta-blockers can be compromised when given in high doses or due to drug-drug interactions.^10-12 Notably, metoprolol succinate and bisoprolol lose their cardio-selectivity in doses over 100 mg and 20 mg, respectively.^10,11 Furthermore, patients with COPD and HF often have other co-morbidities and may require multiple medications to control their symptoms. As a result, these specific patient populations are prone to multiple drug-drug interactions, which may cause a loss of cardio selectivity (Table 1). Therefore, clinicians stay away from using optimal doses of beta-blockers in patients with both COPD and HF.

 

Table 1. Beta-Blockers Prescribing Information Summary^11-18

Beta-Blockers	Beta1-selectivity	Drug interaction	Warning/Contraindication in COPD
Carvedilol*	No	P-glycoprotein substrate and inhibitor	Use with caution. Contraindicated in previous history of bronchospasm
Labetalol	No	Cimetidine	COPD: No study. Should not be used. C/I in asthma and acute bronchospasm
Nadolol	No	Reserpine	Should not in general receive beta-blocker. Use with caution.
Propranolol	No	CYP 2D6, 1A2 and 2C19 substrate	Should not in general receive beta-blocker. Use with caution.
Metoprolol Succinate*	Yes	Reserpine, MAO inhibitors. CYP2D6 inhibitor→ 2-5 fold increase	Should not in general receive beta-blocker. Beta1 selectivity is not absolute. Use lowest possible dose. Bronchodilator should be readily available. Loses cardio-selectivity >100 mg daily10
Bisoprolol*	Yes	Reserpine	Should not in general receive beta-blocker. Beta1 selectivity is not absolute. Use lowest possible dose (2.5 mg QD). Bronchodilator should be readily available. Loses cardio-selectivity at 20 mg11
Nebivolol	Yes	CYP2D6 Inhibitor	Should not in general receive beta-blocker.
Atenolol	Yes	Reserpine	Should not receive beta-blocker. Beta1 selectivity is not absolute. Start with the minimum dose 50 mg QD

*Approved for HF

 

A randomized, double-blind, placebo-controlled, crossover study showed that propranolol 80 mg (a non-selective beta-blocker) reduces FEV₁ and bronchodilator responses to beta-agonist while the metoprolol 100 mg (beta₁-selective beta-blocker) does not ¹⁹. Furthermore, a double-blind, randomized, three-way crossover study conducted by Chang and colleagues showed that metoprolol 195 mg and propranolol 80 mg daily are associated with significantly lower bronchodilator response compared to metoprolol 95 mg daily.²⁰ Besides, participants in the metoprolol 195 mg group showed less exercise tolerance and significantly reduced oxygen saturation compared to participants in the metoprolol 95 mg group. However, these studies had very few patients (n=15 and 14, respectively) and a one-week follow up period. Therefore, it is uncertain whether the diminished bronchodilator response and reduced oxygen saturation are clinically significant and outweigh the benefits of beta-blockers in HF patients.

Despite these concerns, COPD patients may often present with a compelling indication for using beta-blockers, especially when patients have ischemic heart disease or heart failure. In a ten-year (2001-2010) retrospective cohort study of 5977 COPD patients over the age of 50, Short and colleagues demonstrated that beta-blockers have no deleterious effects on lung function.⁷ In addition to cardiovascular benefit from beta-blockers, this study also showed that beta-blockers reduce mortality (22% reduction compared to non beta-blocker group; 95% CI: 0.67 to 0.92), COPD exacerbation and hospitalization when added to established therapy for COPD.  Although majority of the patients (88%) in this study used cardio selective beta-blockers, no significant difference in outcomes was observed.⁷ A Cochrane meta-analysis of 20 studies conducted by Hawkins and colleagues showed that FEV₁ is unaffected by single dose or longer duration of cardio-selective beta-blockers (-1.8% and -1.26% respectively).²¹ Although cardio-selective beta-blockers are safe in stable COPD patients as seen in this study, very little is known about their effects on patients with deteriorating lung function or acute respiratory failure (ARF). Kargin and colleagues in a retrospective (2011-2012) case-control study of 188 patients in a ICU setting showed that beta-blocker use for heart rate control in COPD patients with ARF have similar ICU stay length (median: 6 days in case group vs. 7 days in control group) and mortality (17.6% vs. 15.8%; p = 0.75) compared with COPD patients treated with other heart rate limiting drugs.²² Although all of these studies have suggested that cardio-selective beta-blockers are relatively safe and do not cause clinically significant airway obstruction, COPD exacerbation, or reduction in quality of life, we need to bear in mind that they are conducted retrospectively for a short period of time. Therefore, we still need well-designed, prospective studies to further evaluate the benefit of using beta-blockers in HF patients.

The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for HF does not make specific recommendations regarding patients with COPD and HF, except cautionary^{21, 23}.  In contrast to the ACCF/AHA guideline, European Society of Cardiology Heart Failure guideline provides a more specific recommendation by stating that beta-blockers are not contraindicated in patients with COPD and that cardio-selective beta-blockers could be used in this patient population.²⁴ The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline states that the benefit of using a cardio-selective beta-blocker even in patients with severe COPD outweighs the risk of bronchospasm.²⁵ It also recommends using a beta₁-selective beta-blocker, especially bisoprolol, in COPD patients since bisoprolol was found to have favorable respiratory parameters such as beneficial effect on lung function, minimal deleterious effect on COPD symptoms and improved quality of life.²⁵ The ACCF/AHA also recommends bisoprolol, suggesting a starting dose of 1.25 mg daily and titration up to a maximum of 10 mg daily for patients with HF.²³ Therefore, based on these guidelines, bisoprolol could be recommended in patients with concomitant COPD and HF.

The combination of COPD and HF poses a unique challenge to clinicians. Clinicians need to be aware that bisoprolol loses its selectivity at 20 mg daily and metoprolol loses selectivity over 100 mg daily. Clinicians also need to monitor these patients carefully, since drug-drug interactions may cause beta-blockers to lose their cardio-selectivity. Recent evidence suggests that using cardio-selective beta-blockers in COPD patients is not contraindicated, and that they may decrease mortality in patients with concomitant COPD and HF. It is our duty as pharmacists to make sure that patients with concomitant COPD and HF receive the appropriate beta-blockers at optimal doses.

 

SOURCES:

1. Hoyert DL, Xu J. National vital statistic reports. http://www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_06.pdf. Accessed November 01, 2014
2. Hardie JA, Vollmer WM, Buist AS, Bakke P, Morkve O. Respiratory symptoms and obstructive pulmonary dsease in a population aged over 70 years. Respir Med.2005;99:186-195
3. Iversen KK, Kjaergaard J, Akkan D et al. Chronic obstructive pulmonary disease in patients admitted with heart failure. J Intern Med. 2008;264:361-369
4. Le JT, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with coexistence chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol. 2007;49(2):171-180
5. Gottlieb SS, McCarter RJ, Vogel RA. Effects of beta-blockade on mortality among high-risk and low-risk patients after myocardial infraction. N Engl J Med.1998;339:489-97
6. Egred M, Shaw S, Mohammed B, et al. Under-use of beta-blockers in patents with ischemic heart disease and concomitant chronic obstructive pulmonary disease. Q J Med.2005;98:493-7
7. Short PM, Lipworth SW, Elder DJ, Schembri S, Lipworth BJ. Effects of B-blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ. 2011;342:d2549
8. Kargin F, Takir HB, Salturk C, et al. The safety of beta-blocker use in chronic obstructive pulmonary disease patients with respiratory failure in the intensive care unit. Multidisciplinary Respiratory Medicine.2014;9:8
9. Chang CL, Mills GD, McLachlan JD, Karalus NC, Hancox RJ. Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise. Intern Med J. 2010 Mar;40(3):193-200.
10. AHFS Drug Information. Metoprolol succinate/metoprolol tartrate. Bethesda, MD: American Society of Health-System Pharmacists; 2010. p.1875-84
11. Zebeta (bisoprolol fumarate) [package insert]. Pomona, NY; Duramed Pharmaceuticals, Inc.; Revised 11/2010.
12. Toprol XL (metoprolol succinate) [package insert]. Wilmington, DE; AstraZeneca; Revised 05/2015.
13. Coreg (carvedilol) [package insert]. Research Triangle Part, NC; GlaxoSmithKline; Revised 04/2013.
14. Labetalol [package insert]. Sagent Pharmaceuticals, IL. September 2012.
15. Corgard (nadalol) [package insert]. Pfizer Inc, NY, NY. July 2013.
16. Inderal (propanolol) [package insert]. Cranford, NJ; Akrimax Pharmaceuticals, LLC; Revised 11/2010.
17. Bystolic (nebivolol) [package insert]. St. Louis, MO; Mylan Laboratories, Inc.; Revised 1/2014.
18. Atenolol [package insert]. Pack Pharmaceuticals LLC, Buffalo Grove, IL. January 2013.
19. Woude HJ, Zaagsma J, Postma DS et al. Detrimental effects of B-blockers in COPD: a concern for nonselective B-blockers. CHEST. 2005;127:818-24
20. Chang CL, Mills GD, McLachlan JD, Karalus NC, Hancox RJ. Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise. Internal Medicine Journal. 2010;40:193-200
21. Hawkins NM, Huang Z, Pieper KS et al. Chronic obstructive pulmonary disease is an independent predictor of death but not atherosclerotic events in patients with myocardial infraction: analysis of the Valsartan in Acute Myocardial Infraction Trial (VALIANT). Eur J Heart Fail.2009;11:298-8
22. Kargin R, Takir HB, Salturk C, et al. The safety of beta-blocker use in chronic obstructive pulmonary disease patients with respiratory failure in the intensive care unit. Multidisciplinary Respiratory Medicine. 2014;9:8
23. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation. 2013;128:e240-e327
24. McMurray JJ, Adamopoulos S, Anker S et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. Eur Heart J.2012;33:1787-1847
25. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014. Available from: http://www.goldcopd.org/.

[pubmed_related keyword1=”COPD” keyword2=”beta” keyword3=”blocker”]

Published by Rho Chi Post