Abstract

Background: New advances have been made in medicine, but the incidence and prevalence of Chronic Obstructive Pulmonary Disease (COPD) are evident, and it is established as the fourth cause of death in the United States representing a high cost for the healthcare system. This condition has been related to atrial fibrillation due to the changes in the lungs and vasculature. Based on this history, we seek to evaluate the outcome of AF in the patients with COPD and its relationship with medical therapy utilized to treat this pulmonary condition with the objective of establishing the relationship between the use of beta-agonist therapy for obstructive airway disease in patients with AF.

Discussion: Cell receptors participate in multiple reactions and the sympathetic response is received via the alpha- and beta-receptors are related to the hemodynamic of the vasculature of the lungs and cardiovascular system. The beta-blockade agents are one of the most common medication classes used for rate control in cardiac arrhythmias, but the side effect could be COPD exacerbation; on the other hand, beta-adrenergic or beta-agonist as a therapy for this pulmonary condition could increase the heart rate leading to AF decompensation. There is a clear dilemma in our patients who have airway disease and AF since the treatment for one might worsen the other. The clear benefit in morbidity and mortality of beta-blocker therapy, especially beta1-selective, outweighs the potential for any pulmonary side-effects related to ex-acerbation of COPD or airway disease.

Conclusion: There is clear data showing the evidence of the potential paradoxical side-effect between COPD and AF therapies, given the exacerbation of one due to treatment of the other, benefits versus risks should be discussed and the medical decision should be made based on them. The deteriorated cardiac condition can rapidly predispose to critical complications leading to death, which is why the use of beta-blockade agents will be chosen over possible complications with pulmonary disease. In other words, the benefit should outweigh the risk based on the best outcome for the patient.

Keywords: atrial fibrillation; pulmonary disease; obstructive pulmonary disease; chronic obstructive pulmonary disease (COPD); B-Agonist; B-Block (selective; non-selective); digitalis; other antiarrhythmic.

Citation: Miguel R, Siddharth C, Timothy V. The role of beta-agonist therapy for chronic obstructive airway disease in patients with coexistent atrial fibrillation: Literature review. J Clin Images Med Case Rep. 2021; 2(6): 1416.

Introduction

The new era in cardiovascular diseases has come with great advances in the diagnosis and management of arrhythmias. It is well known that electrophysiology procedures such as ablation and mapping now have different newer approaches.

During the recent decades the world has faced the epidemiological change from acute and infectious disease as first cause of death to the chronic diseases, given the new treatment and advances in medicine, these conditions have not only occupied the first positions as cause of death worldwide, they are also leading the list of most common condition for disability causing a disproportional cost in the health system and creating a critical crises in our community due to the conflict between the severity, medications and copayments.

Due to the increasing incidence and prevalence of Chronic Obstructive Pulmonary Disease (COPD), the Center for Disease Control (CDC) has established it has the fourth cause of death in the United States and one of the conditions of highest cost. The cost is directly proportional to the severity of the disease, especially in those patients who are on multiple inhalation therapy, nebulization, oral agents, oxygen supplementation, and also rehabilitation requirements as we could see this disease could tremendously affect the quality of life of our patients. This condition is a chronic, progressive inflammatory process affecting the lungs and consequently causes changes in the dynamics of the pulmonary blood vessels.

As established by the “International Journal of COPD,” the chronic obstructive pulmonary disease is associated with arrhythmias, more specifically Atrial Fibrillation (AF), an arrhythmia that in more than 90% of the cases originates in the pulmonary veins [1]. Taiwan was one of the first countries relating AF and COPD, finding that patients with COPD had more hospital readmissions and more prevalence of cardiovascular disease including diabetes mellitus, dyslipidemia, hypertension as well as cerebrovascular accidents and congestive heart failure [2].

AF could be described as an age-related arrhythmia that would be associated with several co-morbidities and its mortality can be up to 5% per year despite treatment including addressing the anticoagulation therapy for potential complications like the increased risk of stroke; cardiac events, sudden death, heart failure, and myocardial infarction are frequently seen in patient with this arrhythmias, but one-third of deaths are due to non-vascular causes like cancer, respiratory diseases, and infections, then the remaining AF patients die from stroke or hemorrhage (Approximately 6% each), or other causes [3]. The ENGAGE AF-TIMI 48 trial has found that sudden cardiac death was the single most common cause of death and responsible for approximately a third of all deaths and probably half of all cardiovascular deaths in atrial fibrillation patients; the most common factors related to sudden cardiac death in these patients were: male, left ventricular hypertrophy in the electrocardiogram, ejection fraction <50%, New York Heart Association functional class III‒IV and prior myocardial infarction, non-use of beta blockade agents, use of digitalis and tachycardia [4]. According with WebMD patients with AF could reach over 750,000 admission per year, consuming $8,705 extra yearly and the national total amount could reach 26 billion and 75% of this is related to admissions, the social security office reports AF as a cause of disability due to persistent symptoms [5].

In the other hand, the Center for Disease Control and Prevention have reported that chronic lower respiratory disease, mainly chronic obstructive pulmonary disease, is the fourth leading cause of death in the US, its prevalence is directly related with tobacco smoke as the primary cause, but also the exposure to secondhand smoke, fumes, and genetics are also importantly related [6].

Based on the historic correlation between AF and its origin in the pulmonary blood vessels, its relation with the homodynamic, the importance of the rate or rhythm control, and the relation between COPD, its treatment and the changes produced in the lungs and pulmonary vasculature, we seek to evaluate the outcome of AF in the patients with COPD and its relation with medical therapy utilized to treat this pulmonary condition.

Objective

Our objective is to establish the relationship between the use of beta-agonist therapy for obstructive airway disease in patients with atrial fibrillation, then correlate their role in the exacerbation of this arrhythmia and its outcome.

Method

This is a descriptive retrospective review of thirty-five studies to determine the outcome of patients with AF who use betaagonist therapy for COPD. The studies reviewed were obtained from The Center for Disease Control and Prevention, New England Journal of Medicine, The Lancet Journal, International Journal Chronic Obstructive Pulmonary Disease, StatPearls Internet Publishing, Respiratory Medicine, Journal of the American College of Cardiology, American Journal Respiratory Critical Care Medicine, Proceedings of the National Academy of Sciences of the United States of America, Journal of Cardiothoracic Surgery, Journal of the American Medical Association Internal Medicine, CHEST Journal, Annals of Thoracic Surgery, European Journal of Cardiothoracic Surgery, Dovepress Open Access, Cochrane Database of Systematic Reviews, cvpharmacology.com, and The First Aid For The USMLE Step 1 2019 by McGraw-Hill Education.

Discussion

The pulmonary dynamics are based in bronchoconstriction and bronchodilation, managed by the signaling received in via cell receptors. Multiple factors could affect the course of COPD, promoting exacerbation and potential complications; these could be infections, environmental contaminant, medications side effects, or non-compliance with medications. Besides the multiple reasons for complication, most of them have a common denominator, which is the cell receptors interaction as the cause.

These cell receptors participate in multiple reactions in different organ systems and the sympathetic response is received via the alpha- and beta-receptors. The mechanism of beta-receptors is related to ATP-cAMP conversion via adenylyl cyclase for protein kinase A. This results in calcium influx into myocardial cells and inhibition of myosin light chain kinase in smooth muscle cells. These receptors are responsible for increasing contractility, heart rate, lipolysis and renin release via beta1 -receptors; bronchodilatation, ciliary relaxation, decrease uterine tone, increase of aqueous humor, insulin release, lipolysis and vasodilatation via beta2 -receptors; and increase in thermogenesis of skeletal muscle, lipolysis and urinary bladder relaxation via beta3 -receptors (Table 1) [7]. Since both heart rate and rhythm control are equally effective in AF therapy, most of the time our goal is to control heart rate [8,9]. The reason beta-blockade agents have an important role in the treatment of these arrhythmias is due to its blockade effects of both beta1 - and beta2 - receptors, resulting in heart rate reduction. On the other hand, airway diseases such as COPD, require beta-adrenergic therapy to stimulate the beta2 -receptors preventing further bronchospasm and producing bronchodilatation [10,11].

Beta-blockade agents are one of the most common medication classes used for rate control in cardiac arrhythmias, but their effects are not limited to the cardiovascular system [12]. They are further classified as selective referring to the beta1 - receptor and non-selective which means both beta1 - and beta2 - receptors; the latter might cause bronchoconstriction due to blockade of the beta2 moiety [13]. Given the variety of betablockers available, however, we have the possibility to choose a beta1 -selective blocker, and in theory it should not have any significant effect on the lungs (Table 2.1,2.2) [14].

Table 2.1: Beta Blockade Agents.

Table 2.2: Beta Blockade Agents.

We could summarize the mechanism and use of this agent as:

Decrease of SA and AV nodal activity due to the decrease in CAMP and calcium current.

Used for supra ventricular tachycardia, ventricular rate control for atrial fibrillation and atrial flutter.

Decrease oxygen consumption due to the decrease in heart rate and contractility

Related to decrease in mortality in myocardial infarction.

Proven to reduce the mortality in heart failure (Metoprolol, bisoprolol, carvedilol)

Most common side effects: COPD Exacerbation, impotence, bradycardia, atrioventricular blockade, masking of the symptoms of hypoglycemia, dyslipidemia (Specially Metoprolol), sedation and sleep alterations. Exacerbation of Prinzmetal angina (Propanolol).

Similarly, the effect of beta-adrenergic or beta-agonist use is not limited to the lungs [15]. Its effect reflects the increase in heart rate, myocyte contractility and release of renin given the rebound effect in higher blood pressure, increase in heart rate and cardiac demand, thereby providing an ideal environment for AF decompensation from a cardiovascular perspective and due to the polypharmacy and high incidence of atrial fibrillation in the elderly population, it is important to recognize drugs or other agents as a potential cause and it would contribute to a diagnosis and management of drug-induced AF more efficiently [16]. The treatment with bronchodilator and the frequency of them would depend in the persistency or severity of the obstructive pulmonary disease as well as the cause of the exacerbation of the symptoms (Algorithm 2). The local pulmonary treatment is addressed with the bronchodilators, which could be short acting or long acting (Table 3,4).

Table 3: Beta Adrenergic Agents.

There is a clear dilemma in our patients who have airway disease and AF since the treatment for one might worsen the other. On one side we have the need to break the bronchoconstriction with a bronchodilatory agent which stimulates the beta receptors causing as consequence a potential increase of heart rate, but on the other side, we have the atrial fibrillation requiring beta-blockade agent to control the rate, but these agents will potentially promote a bronchoconstriction blocking the beta adrenergic signaling. These discrepancies in the effects of pharmacotherapy between both conditions explain the high tolerance for beta-blockers in COPD patients who are actively utilizing aerosolized beta2 -agonists [17]. Multiple theories and hypotheses have been exposed while some authors have related the long acting beta adrenergic or the chronic use of beta agonist to less adverse events related with cardiac arrhythmias, Bond et al demonstrated that acute therapy with beta-blockade increased bronchoreactivity, while chronic therapy did not; they described acute therapy as 28 days or less [18].

The side-effects could vary between cases, due to baseline arrhythmia control and how critical or severe the COPD exacerbation might be. The literature has shown different results in specific cases or types of patients, such as those surgical and/ or critically ill where both therapies (beta-blockers and betaagonists) have been highly needed and used. Yamanashi et al showed the potential benefit of beta-agonists post-operatively in patients undergoing thoracic surgery due to malignancy in COPD patients. In their study, the administration of beta-agonist therapy did not show any increase in the incidence of AF chronic obstructive pulmonary disease patients underwent lobectomy or segmentectomy due to non-small-cell lung cancer [19]. Other investigators reported that older individuals with COPD who were new users of long-acting β-agonists and anticholinergics were associated with increased risks of cardiovascular events, reason why they conclude that close monitoring of COPD patients requiring long-acting bronchodilators is needed regardless of drug class; in other words there is an increased risk of cardiovascular events in the presence of beta-agonist treatment [20]. In a cohort of 5226 Holter Monitor COPD patients, 40% had atrial tachycardia. Hanrahan et al showed that patients with COPD have an increased incidence of atrial tachycardia in the presence of long-acting beta-agonists, in this large cohort atrial tachycardia increased by 2%-5% with LABA treatment but more serious arrhythmias were infrequent and did not increase with inhaled LABA therapy, the administration of this medication did not increase mean heart rate [21].

Pauwel et al concluded that the use of formoterol with 100 µg bid or a four times higher dose (400 µg bid) of the ICS budesonide showed a significant decrease in severe exacerbation of asthma [22], while O'Byrnes et al described the improvement of the patient with mild persistent asthma after formoterol was added to budesonide [23].

Following patients with pulmonary malignancy or thoracic surgery, AF has been noted. The reason why both can be considered as risk factors for the development of post-operative atrial arrhythmias [24] might be elucidated by an increase in vagal tone, cardiac inflammatory process, pulmonary dynamics, right heart anomalies and hypoxia [25,26].

In our hospital facility, a retrospective review of 46 of patients with established Atrial Fibrillation (AF) and airways disease on Beta Agonist therapy was conducted and presented in HFSA 2020, were elderly (28 pts were 65 or above), minority (38pts were Black/African American and Hispanic) patients were predominant. 52% of patients had pulmonary hypertension, and 27 pts had Heart Failure (HF). A total of 16pts had COPD, of which 11 were on Beta-Blockers (BB). Overall, BB was used in 60.86% pts (24 Selective vs. 4 Non-Selective). A total of 11 pts had recurrent hospitalization (RH); HF exacerbation was the most common cause with 36% (4pts), followed by AF-RVR 27.27% (3pts). The 63.63% (7pts) were on Beta Blocker; 45.45% (5pts) had PHTN; 27.27% (3pts) had COPD on Beta-Blockers. Regarding the patients with COPD on BB shown to tend Recurrent Hospitalization (RH), there were not patients with COPD who were not on BB with RH. In our data, there was a clear relationship between atrial fibrillation with coexistence heart failure on beta-blocker therapy and re-hospitalization. Beside the chronic obstructive pulmonary disease has been related to structural and hemodynamic cardiac affections, in our review, it did not show a major impact regarding re-hospitalization.

The clear benefit in morbidity and mortality of beta-blocker therapy directed to multiple comorbidities like cardiac arrhythmias and heart failure (Table 5,6) [27-30]; especially beta1 -selective, outweighs the potential for any pulmonary side-effects related to exacerbation of COPD or airway disease [31].

Table 5:Evidence Based, Beta Blockade.

Table 6: Evidence Based, Beta Adrenergic.

Upon literature review, we found significant data focusing on the beta-blockade aspect of the pharmacotherapy for atrial fibrillation (Table 5). Affirm trial published in 2002 was one of the first randomized, multi-center trials where 4060 patients were enrolled and they concluded that there was no survival benefit with the rhythm, control strategy, Rate control was preferable over rhythm control due to lower risk of adverse effects. RACE II trial another multi-center randomized control trial which enrolled 614 patients. Results showed that lenient rate control (<110BPM) was non-inferior to strict rate control (<80bpm), and it was much easier to achieve. The benefits of Beta blockade were applied to patients with heart failure in the CIBIS-II trial published in 1999. This trial was stopped early as interim analysis showed significant mortality benefit in heart failure with reduced ejection fraction with NYHA class III and Class IV symptoms. In 2003, Results of the COMET trial were published which showed significant superiority interns of survival benefit for Carvedilol (Combined alpha-1 and nonselective beta-blocker) over metoprolol (Competitive, beta-1 selective/ cardioselective adrenergic antagonist) when used in the treatment of chronic heart failure with reduced LV ejection fraction.

There was very limited research on the role of beta-agonist therapy in COPD/Atrial fibrillation. Shah V, et al in 2016 suggested correcting the underlying respiratory decompensation while treating patients with Atrial fibrillation as they render the treatment of AF ineffective and that presence of AF is a predictor for increased mortality for COPD-related hospitalizations. Chen CY et al enrolled 882 patients with both COPD and AF along with 2646 patients with COPD without AF and analyzed hospitalization outcomes and concluded that the length of hospital stays and the in-hospital mortality rate were significantly higher in AF patients with COPD than in those without COPD. There were no specific outcomes related to the use of beta-agonist therapy in either group. Van Gestel YR et al evaluated the use of beta blocker therapy in 3371 consecutive patients in a single institution who underwent major vascular surgery and results showed that in carefully selected patients with COPD, the use of cardioselective beta-blockers appears to be safe and associated with reduced mortality. The most closely related analysis was by Yamanashi, K et al in 2017 where they retrospectively analyze 174 COPD patients who were administered Beta-2 agonist therapy perioperatively while undergoing lobectomy or segmentectomy. Increased incidence of postoperative atrial arrhythmias including Atrial fibrillation was not observed (Table 6).

As outlined in table 4, several landmark clinical trials have proven the mortality benefit of Beta-blockers in heart failure patients especially reduced ejection fraction, reason why it is established as a first-line therapy and must be prescribed as a part of pharmacological therapy in the absence of contraindications.

Table 4: Beta Adrenergic Agents

The cardiac remodeling observed in heart failure occurs due to the structural and functional changes as a cause of molecular and cellular changes involving cardiac myocytes. One of the reasons for these changes is the chronic stimulation of Beta 1- adrenergic receptors, the same stimulus that is inhibited by beta blockers [32-35].

Beta blockade therapy works improving the outcome of patients with cardiomyopathy via multiple modalities including decreasing the deleterious effects of catecholamine stimulation on the myocytes, also increases the responsiveness of the myocardium to inotropic and chronotropic function and thus improves contractility by upregulating beta-1 receptor density in the myocardium [36,37].

Although both COPD and atrial fibrillation have existed for a long time and there is substantial research in both, there is not enough evidence in the concurrent management of the complex co-presentation. The most significant being the lack of Randomized clinical trials. We recommend there is a role for future studies focusing on populations with co-existing COPD and atrial fibrillation like the one conducted by Chen CY et al with further emphasis and subgroups based on the level of each disease namely advanced COPD requiring home oxygen therapy. Atrial fibrillation can be sub-grouped based on comorbidities like heart failure, history of stroke, etc, and outcomes based on beta-agonist therapy.

Conclusion

There is no doubt about the relation between atrial fibrillation and cardiac events in the presence of comorbid (Age, sex, heart failure, persistent arrhythmia, etc) and medication side effects; clear data have shown the evidence of the potential paradoxical side-effect between COPD and AF therapies, given the exacerbation of one due to treatment of the other, reason why benefits versus risks should be discussed and the medical decision has to be taken based on them. Elderly population has a higher risk for side effects, the main reason for this is the higher incidence of arrhythmias especially atrial fibrillation and potential side effect from the polypharmacy in this population, reason why the fast recognition of the potential side effects and exacerbation of the any arrhythmia in a timely matter is highly important, as well as the consideration for alternatives therapies like digoxin, calcium channel blockers [39,40], or amiodarone [41]. Deteriorated cardiac condition can rapidly predispose to critical complications leading to death, which is why the use of beta-blockade agents will be chosen over possible complications with pulmonary disease based on the morbidity and mortality benefit. The clinician must establish the risk based on the on the possible complications like risk of stroke (Current ECG, CHADS2-VASc and NIHSS scores could be used), respiratory failure (CAT Score could be used), or exacerbation of their baseline conditions. In other words, and besides further data would be needed in this population of patients, the benefit should outweigh the risk based on the best outcome for the patient.

References

1. Shah V, Desai T, Agrawal A. The Association between Chronic Obstructive Pulmonary Disease (COPD) and Atrial Fibrillation: A Review. Chron Obstruct Pulmon Dis. 2016; 1: 2.
2. Chen CY, Liao KM. The impact of atrial fibrillation in patients with COPD during hospitalization. 2018: 13; 2105-2112.
3. Antonio Gómez-Outes, Maria Luisa Suárez-Gea, Jose Manuel García-Pinilla. Causes of death in atrial fibrillation: Challenges and opportunities, Trends in Cardiovascular Medicine. 2017; 27: 494-503.
4. Robert P Giugliano, Christian T Ruff, Eugene Braunwald, Sabina A Murphy, Stephen D Wiviott, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. 2013; 369: 2093-2104.
5. This information could be found at: https://www.disabilitybenefitscenter.org/social-security-disabling-conditions/atrialfibrillation#:~:text=AFib%20can%20be%20considered%20 a,in%20the%20SSA’s%20Blue%20Book.
6. This information could be found at: https://www.cdc.gov/dotw/ copd/index.html#:~:text=Chronic%20lower%20respiratory%20 disease%2C%20mainly,genetics%20can%20also%20cause%20 COPD.
7. Tao Le, et al. The First Aid For The USMLE by McGraw-Hill Education. 2019.
8. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, et al, Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002; 347: 1825-33.
9. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, et al. Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002; 347: 1834-40.
10. Kew KM, Mavergames C, Walters JAE. Long-acting beta-agonists for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews. 2013; 10: CD010177.
11. Salpeter SR. Bronchodilators in COPD: impact of beta-agonists and anticholinergics on severe exacerbations and mortality. Int J Chron Obstruct Pulmon Dis. 2007; 2: 11-18.
12. Farzam K, Jan A. Beta Blockers. [Updated 2020 Nov 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 2020.
13. Klabude, Richard E PhD. CArdiovascular Pharmacology Concepts. https://www.cvpharmacology.com/cardioinhibitory/ beta-blockers
14. Salpeter SR, Buckley NS. Use of β-blockers and β-agonists in COPD: A review of clinical outcomes. Respiratory Medicine: COPD Update. 2007; 2: 133-139.
15. Hsu E, Bajaj T. Beta 2 Agonists. [Updated 2020 Jun 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 2020.
16. Cornelis S. van der Hooft et al. Drug-induced atrial fibrillation, Journal of the American College of Cardiology, 2004; 44: 2117- 2124.
17. http://w w w.sciencedirect.com/science/article/pii/ S0735109704017437
18. van Gestel YRBM, Hoeks SE, Sin DD, Welten GMJM, Schouten O, et al. Impact of cardioselective β-blockers on mortality in patients with chronic obstructive pulmonary disease and atherosclerosis. Am J Respir Crit Care Med. 2008; 178: 695-700.
19. Callaerts-Vegh Z, Evans KL, Dudekula N, Cuba D, Knoll BJ, et al. Effects of acute and chronic administration of beta-adrenoceptor ligands on airway function in a murine model of asthma. Proc Natl Acad Sci U S A. 2004; 101: 4948-4953.
20. Yamanashi K, Marumo S, Sumitomo R. et al. Long acting β2- adrenoceptor agonists are not associated with atrial arrhythmias after pulmonary resection. J Cardiothorac Surg. 2017; 12: 35.
21. Gershon A, Croxford R, Calzavara A, To T, Stanbrook MB, Upshur R, et al. Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease. JAMA Intern Med. 2013; 173: 1175-85.
22. Hanrahan, John P, Grogan, Donna R, Baumgartner Rudolf A, Wilson Amy, Cheng, Hailong MS, et al. Arrhythmias in Patients With Chronic Obstructive Pulmonary Disease (COPD), Medicine. 2008; 87: 319-328.
23. Pauwels RA, Löfdahl CG, Postma DS, Tattersfield AE, O’Byrne P, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. The New England journal of medicine. 1997; 337: 1405-1411.
24. O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom T. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. American journal of respiratory and critical care medicine. 2001; 164: 1392-1397.
25. Sekine Y, Kesler KA, Behnia M, Brooks-Brunn J, Sekine E, et al. COPD may increase the incidence of refractory supraventricular arrhythmias following pulmonary resection for non-small cell lung cancer. Chest. 2001; 120: 1783-90.
26. Ritchie AJ, Bowe P, Gibbons JR. Prophylactic digitalization for thoracotomy: a reassessment. Ann Thorac Surg. 1990; 50: 86-8.
27. Rena O, Papalia E, Oliaro A, Casadio C, Ruffini E, Filosso PL, Sacerdote C, Maggi G. Supraventricular arrhythmias after resection surgery of the lung. Eur J Cardiothorac Surg. 2001; 20: 688-93.
28. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999; 353: 9-13.
29. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, et al. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002; 347: 1825-33.
30. Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, et al. RACE II Investigators. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010; 362: 1363-73.
31. Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, et al. Carvedilol Or Metoprolol European Trial Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003; 362: 7-13.
32. Albouaini K, Andron M, Alahmar A, Egred M. Beta-blockers use in patients with chronic obstructive pulmonary disease and concomitant cardiovascular conditions. Int J Chron Obstruct Pulmon Dis. 2007; 2: 535-40.
33. Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. AustraliaNew Zealand Heart Failure Research Collaborative Group. J Am Coll Cardiol. 1997; 29: 1060-6.
34. Groenning BA, Nilsson JC, Sondergaard L, Fritz-Hansen T, Larsson HB, Hildebrandt PR. Antiremodeling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol. 2000; 36: 2072-80.
35. Kramer DG, Trikalinos TA, Kent DM, Antonopoulos GV, Konstam MA, et al. Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction: a meta-analytic approach. J Am Coll Cardiol. 2010; 56: 392-406.
36. Koitabashi N, Kass DA. Reverse remodeling in heart failure-- mechanisms and therapeutic opportunities. Nat Rev Cardiol. 2011; 9: 147-57.
37. Bristow MR. beta-adrenergic receptor blockade in chronic heart failure. Circulation. 2000; 101: 558-69.
38. Joseph P, Swedberg K, Leong DP, Yusuf S. The Evolution of β- Blockers in Coronary Artery Disease and Heart Failure (Part 1/5). J Am Coll Cardiol. 2019; 74: 672-682.
39. Fauchier L, Laborie G, Clementy N, Babuty D. Beta-blockers or Digoxin for Atrial Fibrillation and Heart Failure?. Cardiac failure review. 2016; 2: 35-39.
40. Scheuermeyer FX, Grafstein E, Stenstrom R, Christenson J, Heslop C, et al. Safety and efficiency of calcium channel blockers versus beta-blockers for rate control in patients with atrial fibrillation and no acute underlying medical illness. Academic emergency medicine: official journal of the Society for Academic Emergency Medicine. 2013; 20: 222-230.
41. Martindale JL, deSouza IS, Silverberg M, Freedman J, Sinert R. β-Blockers versus calcium channel blockers for acute rate control of atrial fibrillation with rapid ventricular response: a systematic review. European journal of emergency medicine: official journal of the European Society for Emergency Medicine. 2015; 22: 150-154.
42. Solomon AJ, Greenberg MD, Kilborn MJ, Katz NM. Amiodarone versus a beta-blocker to prevent atrial fibrillation after cardiovascular surgery. American heart journal. 2001; 142: 811-815.