Lucian Muresan
email: lmure_san@yahoo.com

PhD Gabriel Cismaru

PhD Crina Muresan

PhD Radu Rosu

PhD Gabriel Gusetu

PhD Mihai Puiu

MD Razvan Olimpiu Mada

MD; MSc Pedro Raphaël

Martins

Beta blockers for the treatment of arrhythmias: Bisoprolol -a systematic review Bêta-bloquants pour le traitement des arythmies: Bisoprolol -une revue systématique AUTHORS' NAMES AND INSTITUTIONAL AFFILIATIONS

Keywords: bisoprolol, beta blockers, arrhythmias, atrial fibrillation, ventricular arrhythmias J o u r n bisoprolol, bêtabloquants, arythmies, fibrillation auriculaire, arythmies ventriculaires

 This is the first systematic review on the role of Bisoprolol, a lipophilic beta 1 selective receptor blocker, for the treatment of arrhythmias.

 Bisoprolol is useful for the treatment of supraventricular arrhythmias, especially for rate control during atrial fibrillation.

J o u r n a l P r e -p r o o f  Evidence also exists for its efficacy in the treatment of ventricular arrhythmias, both in primary and in secondary prevention.

Objectives

Since the first introduction in clinical practice of a beta blocker, propranolol, in 1965 [START_REF] Quirke | Putting theory into practice: James Black, receptor theory and the development of the beta-blockers at ICI, 1958-1978[END_REF], more than 50 different beta blockers have been used for the treatment of both cardiac and non-cardiac conditions. Current uses of beta blockers in the treatment of cardiovascular disease include arterial hypertension [START_REF] Williams | Practice Guidelines for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension[END_REF][START_REF] Whelton | ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines[END_REF], acute coronary syndromes (4-7), chronic coronary syndromes [START_REF] Knuuti | <2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes[END_REF][START_REF] Fihn | ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons[END_REF], post myocardial revascularization [START_REF] Neumann | ESC/EACTS Guidelines on myocardial revascularization[END_REF][START_REF] Patel | ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease : A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery[END_REF], decreased left ventricular function after myocardial infarction [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF], heart failure [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF] and cardiac arrhythmias [START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace : European pacing, J o u r n a l P r e -p r o o f arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the[END_REF][START_REF] January | AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons[END_REF][START_REF] Page | ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society[END_REF][START_REF] Kirchhof | ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS[END_REF][START_REF] Brugada | ESC Guidelines for the management of patients with supraventricular tachycardiaThe Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC)[END_REF][START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society[END_REF].

Although part of the same class of drugs, important differences exist between different beta blockers regarding their chemical structure, route of administration, pharmacokinetic and pharmacodynamic properties (absorption, bioavailability, metabolism, time to effect, elimination route, hydrophilic or liphophilic character, selective or non-selective nature, the presence or absence of intrinsic sympathomimetic activity) and side effects which, at least from a theoretical perspective, may make some beta blockers more appropriate than others for the treatment of cardiac arrhythmias. Indeed, not all beta blockers have the same antiarrythmic properties in patients with long QT syndrome (LQTS), where nadolol and propranolol are to be preferred over other beta blockers [START_REF] Ackerman | Beta-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: Are all betablockers equivalent?[END_REF], and metoprolol should probably be avoided [START_REF] Chockalingam | Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol[END_REF]. This observation raises the question whether all beta blockers are equally efficient in the treatment of arrhythmias, and if not, which beta blockers should be preferred? Also, if a beta blocker is inefficient in the treatment of a arrhythmia, can a different beta blocker be successfully used instead?

The European Society of Cardiology (ESC) and the American Heart Association / American College of Cardiology / Heart Rhythm Society (AHA / ACC / HRS) have published several consensus documents on the use of beta blockers for the treatment of arrhythmias [START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC)Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Europace : European pacing, J o u r n a l P r e -p r o o f arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the[END_REF][START_REF] January | AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons[END_REF][START_REF] Page | ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society[END_REF][START_REF] Kirchhof | ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS[END_REF][START_REF] Brugada | ESC Guidelines for the management of patients with supraventricular tachycardiaThe Task Force for the management of patients with supraventricular tachycardia of the European Society of Cardiology (ESC)[END_REF][START_REF] Al-Khatib | AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society[END_REF]. The 2004 ESC Expert consensus document on beta adrenergic receptor blockers [START_REF] Lopez-Sendon | Expert consensus document on beta-adrenergic receptor blockers[END_REF] provides evidence for the use of atenolol, esmolol, metoprolol, nadolol, propranolol, sotalol, and timolol for the treatment of arrhythmias. Nevertheless, other existing beta blockers may be both safe and efficient for the treatment of both supraventricular and ventricular arrhythmias.

Bisoprolol is a lipophilic beta 1 selective receptor blocker that was patented in 1976 and introduced in [START_REF] Harting | Pharmacodynamic profile of the selective beta 1-adrenoceptor antagonist bisoprolol[END_REF][START_REF] Wellstein | Affinity and selectivity of beta-adrenoceptor antagonists in vitro[END_REF][START_REF] Schliep | Beta 1-selectivity of bisoprolol, a new beta-adrenoceptor antagonist, in anesthetized dogs and guinea pigs[END_REF][START_REF] Klockow | Studies on the receptor profile of bisoprolol[END_REF]. It inhibits both basal and stimulated renin secretion and has antihypertensive properties that are equivalent to the ones of nebivolol [START_REF] Czuriga | Comparison of the new cardioselective beta-blocker nebivolol with bisoprolol in hypertension: the Nebivolol, Bisoprolol Multicenter Study (NEBIS)[END_REF]. It is devoid of serious and unexpected side-effects, even at high doses. Glucose intolerance and sedative effects are less pronounced compared to propranolol [START_REF] Buhring | Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans[END_REF]. It has no significant negative effect of the lipid metabolism [START_REF] Buhring | Pharmacokinetics and metabolism of bisoprolol-14C in three animal species and in humans[END_REF]. Most common side effects are fatigue, bradycardia, hypotension and gastro-intestinal symptoms. Unlike non-selective beta blockers (nadolol, propranolol), it is not associated with a significantly increased risk of asthma exacerbations clinical practice in 1986 [START_REF] Dorow | Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris[END_REF][START_REF] Neuss | Electrophysiologic effects of an acute betablockade induced by bisoprolol in patients with supraventricular tachycardia as assessed by His-bundle electrograms[END_REF][START_REF] Sugimoto | Clinical evaluation of bisoprolol in the treatment of extrasystoles and sinus tachycardia: an interim report[END_REF]. It has a long duration of action, with a slower drop in the action duration curve compared to propranolol [START_REF] Kramer | Comparison of bisoprolol with other betaadrenoceptor blocking drugs[END_REF]. Its half-life is 10-11 hours [START_REF]Balanced pharmacokinetics and metabolism of bisoprolol[END_REF], which allows a single daily administration [START_REF] Lopez-Sendon | Expert consensus document on beta-adrenergic receptor blockers[END_REF]. Common doses range from 1.25 mg to 10 mg daily [START_REF] Lopez-Sendon | Expert consensus document on beta-adrenergic receptor blockers[END_REF]. The maximal approved dose is 20 mg once a day (for the treatment of hypertension). It is devoid of intrinsic sympathetic activity. Its bioavailability from film-coated tablets is about 90%. In plasma, it circulates 30% proteinbound. It is moderately lipid-soluble. Fifty percent of the dose is metabolized by the liver, via CYP3A4. It is eliminated 50% by the kidney, unchanged. Both in vivo and in vitro studies have shown that it is one of the most beta 1 selective beta blockers, more selective than atenolol, betaxolol or metoprolol

J o u r n a l P r e -p r o o f

The aim of this study was to analyze the current existing evidence for bisoprolol in the treatment of arrhythmias, both supraventricular and ventricular.

Material and Methods

Using the keywords "bisoprolol" and either "arrhythmia" or "atrial fibrillation" or "ventricular tachycardia" or "premature ventricular complexes", the Medline database was screened by 2 independent researchers for articles in the English or French language up to April 2020, assessing the role of bisoprolol in the treatment of arrhythmias. Manual additional search was then used in order to identify potential important studies on the efficacy of bisoprolol in the treatment of arrhythmias that were missed using the above-mentioned search strategy. Data was then analyzed according to the type of arrhythmia treated (supraventricular vs. ventricular), the type of results found (positive / negative / mixed) and the quality of evidence (very low, low, moderate, high) using the GRADE approach [START_REF] Guyatt | GRADE: an emerging consensus on rating quality of evidence and strength of recommendations[END_REF]. Prospective randomized clinical trials were considered high quality evidence; retrospective studies on small populations of subjects were considered low quality evidence.

Studies written in languages other than English or French, case reports / case series / studies performed on less than 10 subjects, duplicate titles, studies not relevant to the current topic, abstracts of which manuscripts were not available, review articles, meta-analysis and letter to the editors were not included in the study.

Results

The search strategy identified a number of 325 studies, of which 28 met the inclusion criteria (Figure 1). Among these 28 studies, 19 assessed the role of bisoprolol in the treatment of supraventricular arrhythmias: 1 study assessed the effect of bisoprolol on respiratory sinus arrhythmia, 2 studies assessed the effect of bisoprolol on paroxysmal supraventricular tachycardia, and 1 study assessed the in patients with mild or moderate forms of dieases [START_REF] Morales | Respiratory effect of beta-blockers in people with asthma and cardiovascular disease: population-based nested case control study[END_REF]. Bisoprolol will give a positive result in doping tests.

The CIBIS trial [START_REF]A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees[END_REF] showed that bisoprolol reduces mortality in heart failure patients. However, no significant difference was observed in sudden death rate (17 patients on placebo vs 15 patients on bisoprolol) or death related to documented ventricular tachycardia or fibrillation (7 patients on placebo vs 4 patients on bisoprolol). Contrarily, in the following CIBIS-II trial [START_REF]The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial[END_REF], there were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (48 [3•6%] vs 83 [6•3%] deaths), fact which established its use in patients with heart failure and reduced ejection fraction (HFREF) [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF]. Bisoprolol is currently also used for the treatment of arterial hypertension (2) and myocardial ischemia [START_REF] Williams | Practice Guidelines for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension[END_REF][START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)[END_REF][START_REF]The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial[END_REF]. However, its role in the treatment of arrhythmias is less well established. Unlike other beta blockers (atenolol, metoprolol, nadolol propranolol, sotalol), it is not mentioned in some of the most important international guidelines on the treatment of arrhythmias, such as the 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death [START_REF] Priori | ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)[END_REF]. However, given its positive efficacy/side effects profile, bisoprolol remains one of the most largely-used beta blockers in clinical practice. role of bisoprolol on a mixed population of patients (a part with premature atrial contractions and a part with paroxysmal supraventricular tachycardia); 15 studies evaluated the role of bisoprolol for the treatment of atrial fibrillation, either as part of a rhythm control strategy (post cardioversion of atrial fibrillation or prevention of AF in a high-risk setting, post-surgery) or as a rate control strategy (negative dromotropic effect) either in patients post coronary artery bypass graft (CABG) or non-cardiac surgery, or in a non-post-surgical setting. Nine studies assessing the role of bisorpolol in the treatment of supraventricular arrhythmias compared its efficacy to other beta blockers (carvedilol, landiolol) or other antiarrhythmic drugs (amiodarone, sotalol) or to catheter ablation. Two studies did not find a beneficial effect of bisoprolol for the treatment of specific supraventricular arrhythmias; the rest of the studies identified at least some benefit. The quality of the studies varied from very low (4 studies) to high (3 studies).

There were 8 studies evaluating the role of bisoprolol in the treatment of ventricular arrhythmias. Among these studies, 2 studies evaluated its role in the treatment of premature ventricular contractions, 4 assessed its role in the treatment of patients with myocardial ischemia or heart failure, and 2 assessed the role of bisoprolol in the treatment of patients with long QT syndrome (LQTS). All but one study found positive results of bisoprolol in the treatment of ventricular arrhythmias. The quality of the studies varied from low (3 studies) to high (2 studies).

One study assessed the efficacy of bisoprolol in treating a mixed population of patients, some with supraventricular arrhythmias and some with ventricular arrhythmias (premature ventricular contractions).

A summary of these studies is presented in table 1 and table 2.

Figure 1. Flowchart describing the selection steps of the references used in this review

Table 1. The role of bisoprolol in the treatment of supraventricular arrhythmias -data from clinical studies. * -this study included a mixed population of patients, some with SVT, others with PVC. Only the effect of bisoprolol on patients with SVT is assessed here. For the discussion on this study about the efficacy of bisoprolol in patients with PVC, please see table 2. AF = Atrial Fibrillation; AT = atrial tachycardia; AV = atrio-ventricular; AVRT = atrio-ventricular reentry tachycardia; AVNRT = Atrioventricular node reentry tachycardia; CABG = coronary artery bypass graft; HF = heart failure; HR = heart rate; PAC = Premature atrial contractions; P-AF = Paroxysmal atrial fibrillation; PVC = premature ventricular contractions; QOL = Quality of Life; SR = sinus rhythm; SVT = Supraventricular tachycardia.

Table 2. The role of bisoprolol in the treatment of ventricular arrhythmias -data from clinical studies. * -this study included a mixed population of patients, some with SVT, others with PVC. Only the effect of bisoprolol on patients with PVC is assessed here. For the discussion on this study about the efficacy of bisoprolol in patients with SVT, please see table 1

Discussion

This review focused on assessing the current existing evidence regarding bisoprolol for the treatment of arrhythmias, both supraventricular and ventricular. The main findings can be summarized as follows: regarding supraventricular arrhythmias, 1. bisoprolol is less effective than catheter ablation in preventing recurrences in patients with AVNRT; 2. It is useful as part of a rate control strategy by efficiently lowering heart rate in patients with atrial fibrillation; 3. It is efficient as part of a rhythm control strategy by preventing the onset of atrial fibrillation in patients who have undergone surgery (both cardiac and non-cardiac); 4. Less robust evidence exists concerning its role in pharmacological cardioversion of atrial fibrillation, in preventing AF recurrence after electrical cardioversion and in improving symptoms and quality of life in patients with paroxysmal atrial fibrillation. Regarding ventricular arrhythmias: 1. bisoprolol reduces mortality and is efficient in reducing the number of hospitalizations due to severe arrhythmias (sustained VT or VF) in patients with stable heart failure; 2. Administered early (<4 hours) after myocardial infarction, it lowers mortality, it reduces the number of episodes of ventricular arrhythmias and major adverse cardiac events (MACE) in patients with NSTEMI; 3. It efficiently reduces the ventricular arrhythmia burden in patients with PVC; 4. Its role in treating patients with LQTS is less well established.

Bisoprolol for the treatment of supraventricular arrhythmias

Most of the studies assessing the role of bisoprolol in the treatment of supraventricular arrhythmias focused on its role in the treatment of atrial fibrillation, either in a post-surgical setting or not related to surgery. In a surgical setting, either post CABG or after non-cardiac surgery, all of the evaluated studies addressing this topic (39-44) identified at least some benefit of bisoprolol, with low rates of adverse events, with one study finding a higher efficacy compared to carvedilol [START_REF] Marazzi | Comparison of effectiveness of carvedilol versus bisoprolol for prevention of postdischarge atrial fibrillation after coronary artery bypass grafting in patients with heart failure[END_REF] and another an efficacy equal to that of amiodarone [START_REF] Sleilaty | Postoperative oral amiodarone versus oral bisoprolol as prophylaxis against atrial fibrillation after coronary artery bypass graft surgery: a prospective randomized trial[END_REF]. Bisoprolol was also efficient in decreasing heart rate in patients who developed atrial fibrillation [START_REF] Yasui | Bisoprolol transdermal patch treatment for patients with atrial fibrillation after noncardiac surgery: A single-center retrospective study of 61 patients[END_REF]. A recent Cochrane systematic review confirms these findings, concluding that beta blockers reduce the burden of both supraventricular and ventricular arrhythmias after cardiac surgery, and substantially reduce the burden of supraventricular arrhythmias after non-cardiac surgery [START_REF] Blessberger | Perioperative beta-blockers for preventing surgery-related mortality and morbidity. The Cochrane database of systematic reviews[END_REF]. Concerning bisoprolol, it states that if beta-blockers are started before surgery, bisoprolol may be considered as first choice (class IIb, level of evidence B). In a non-surgical setting, there is weak evidence that bisoprolol prevents recurrence post electrical cardioversion of AF, with bisoprolol being as efficient as sotalol (weak evidence) [START_REF] Plewan | Maintenance of sinus rhythm after electrical cardioversion of persistent atrial fibrillation; sotalol vs bisoprolol[END_REF]. Data regarding its efficacy compared to carvedilol in this setting is mixed [START_REF] Katritsis | Comparison of effectiveness of carvedilol versus bisoprolol for maintenance of sinus rhythm after cardioversion of persistent atrial fibrillation[END_REF][START_REF] Konishi | Comparative effects of carvedilol vs bisoprolol for severe congestive heart failure[END_REF]. In combination with propafenone, it was shown to be efficient in converting AF to sinus rhythm more rapidly compared to propafenone alone (weak evidence), but in this study, the percentage of patients who converted to sinus rhythm after 24 hours was equal in both groups [START_REF] Negreva | Effect of selective beta-blockade with bisoprolol in the treatment of recent-onset atrial fibrillation[END_REF]. Bisoprolol is also efficient in lowering heart rate in patients with atrial fibrillation (50-53), with its transdermal administration being as efficient as iv landiolol [START_REF] Nakamura | Switching therapy from intravenous beta blocker to bisoprolol transdermal patch for atrial fibrillation tachycardia[END_REF] or oral bisoprolol [START_REF] Yamashita | Comparison of heart rate reduction effect and safety between bisoprolol transdermal patch and bisoprolol fumarate oral formulation in Japanese patients with persistent/permanent atrial fibrillation (BISONO-AF study)[END_REF]. There is also some evidence that bisoprolol improves symptoms and quality of life in patients with paroxysmal AF, being well tolerated [START_REF] Ishiguro | Antiarrhythmic effect of bisoprolol, a highly selective beta1-blocker, in patients with paroxysmal atrial fibrillation[END_REF]. Even though the authors of this study state that elimination of AF episodes on ECGs was observed in 84 patients (62%), the efficacy of bisoprolol in the prevention on AF recurrence cannot be assessed based on this study, since there was no control group.

A meta-analysis performed by Nasr et al showed that taken together, carvedilol, bucindolol, metoprolol, nebivolol and bisoprolol prevent the onset of atrial fibrillation in patients with heart failure [START_REF] Nasr | Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis[END_REF]. The evidence for the efficacy of bisoprolol in this setting comes from the CIBIS I and II trials [START_REF]A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees[END_REF][START_REF]The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial[END_REF]. Taking together the evidence on bisoprolol and metoprolol, the authors found a relative risk (RR) reduction of 41% (p = 0.006) for the onset of new atrial fibrillation.

During the past years, catheter ablation has become an established technique for the treatment of atrial fibrillation. Initially, this was considered an alternative technique for patients who presented atrial fibrillation recurrence under antiarrhythmic drugs, which usually included a beta blocker [START_REF] Kirchhof | ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS[END_REF]. Lately, catheter ablation has become the better choice for rhythm control strategy (vs. antiarrhythmic drugs), given the results of latest trials [START_REF] Andrade | Cryoballoon Ablation as Initial Treatment for Atrial Fibrillation: JACC State-of-the-Art Review[END_REF][START_REF] Wazni | Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation[END_REF]. Several studies have demonstrated its superiority to antiarrhythmic drugs for the maintenance of sinus rhythm, regardless of the type of energy used: radiofrequency (59-66) or cryoenergy [START_REF] Andrade | Cryoballoon Ablation as Initial Treatment for Atrial Fibrillation: JACC State-of-the-Art Review[END_REF][START_REF] Wazni | Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation[END_REF]. Beta blockers were largely used in these trials, along with class I (flecainide, propafenone) or class III antiarrhythmic drugs (mostly amiodarone). Explicit references to specific beta blockers were usually not made in these trials. Up to the present date, there is no specific trial focusing on the efficacy of bisoprolol compared to catheter ablation in patients with atrial fibrillation.

Concerning the role of bisoprolol in the treatment of paroxysmal SVT, there is little but solid evidence showing that it is less efficient in preventing AVNRT recurrence compared to catheter ablation [START_REF] Katritsis | Catheter ablation vs. antiarrhythmic drug therapy in patients with symptomatic atrioventricular nodal reentrant tachycardia: a randomized, controlled trial. Europace : European pacing, arrhythmias, and J o u r n a l P r e -p r o o f cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the[END_REF]. In their study, Katritsis et al demonstrated significantly more AVNRT recurrences in the medical treatment group (bisoprolol 5 mg od or diltiazem 120 -300 mg od) vs catheter ablation (p<0.001). Evidence assessing its role in patients atrio-ventricular reentry tachycardia (AVRT) and in patients with atrial tachycardia [START_REF] Neuss | Electrophysiologic effects of an acute betablockade induced by bisoprolol in patients with supraventricular tachycardia as assessed by His-bundle electrograms[END_REF] is limited, since no randomized control trial evaluating the role of bisoprolol was conducted in these patients. Therefore, firm conclusions about its efficacy in this setting cannot be drawn.

Overall, in patients with supraventricular arrhythmias, bisoprolol is efficient in patients with atrial fibrillation both as part of a rhythm control and a rate control strategy in patients undergoing cardiac or non-cardiac surgery. In non-surgical patients, it is efficient as a rate control agent and it likely improves symptoms and quality of life. In patients with AVNRT, it is less efficient than catheter ablation in preventing recurrences.

Bisoprolol for the treatment of ventricular arrhythmias Our search strategy found evidence supporting the use of bisoprolol for the treatment of ventricular arrhythmias, both in patients without structural heart disease (either in otherwise healthy subjects or in patients with channelopathies) and in patients with heart disease, namely myocardial ischemia and heart failure.

The positive impact of ventricular arrhythmia reduction of bisoprolol in patients with heart failure relies on the CIBIS [START_REF]A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees[END_REF] and the CIBIS-II trials [START_REF]The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial[END_REF]. A comprehensive discussion of these studies is outside the purpose of this review and can be found elsewhere [START_REF] Leizorovicz | Bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies--CIBIS and CIBIS II. Cardiac Insufficiency Bisoprolol Study[END_REF]. The CIBIS trial [START_REF]A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). CIBIS Investigators and Committees[END_REF] showed that, bisoprolol reduces mortality in heart failure patients, but not sudden cardiac death (17 patients on placebo vs 15 patients on bisoprolol) nor death related to documented ventricular tachycardia or fibrillation (7 patients on placebo vs 4 patients on bisoprolol, p=ns). However, the following CIBIS-II trial [START_REF]The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial[END_REF], performed on a larger population of patients, found significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (48 [3•6%] vs 83 [6•3%] deaths), demonstrating the efficient antiarrhythmic properties of bisoprolol in a clinical setting.

In patients with acute myocardial ischemia, namely NSTEMI, after adjusting for confounders, Maclean et al [START_REF] Maclean | Effect of early bisoprolol administration on ventricular arrhythmia and cardiac death in patients with non-ST elevation myocardial infarction[END_REF] found that early (less than 4 hours) bisoprolol administration was protective for ventricular arrhythmia (p=0.038, OR 0.114, CI 0.015 to 0.885) and MACE (p=0.011, OR 0.064, CI 0.008 to 0.527), with few adverse effects of Bisoprolol (one episode of symptomatic bradycardia).

Three trials on small populations of patients examined the role of bisoprolol, in patients with PVC [START_REF] Sugimoto | Clinical evaluation of bisoprolol in the treatment of extrasystoles and sinus tachycardia: an interim report[END_REF][START_REF] Kobayashi | Dipyridamole suppresses catecholamine-and Ca++ influx-sensitive ventricular arrhythmias[END_REF][START_REF] Shinohara | Assessment of a novel transdermal selective beta1-blocker, the bisoprolol patch, for treating frequent premature ventricular contractions in patients without structural heart disease[END_REF]. These trials found a significant reduction in the ventricular arrhythmia burden, at doses of 2.5 -5 mg po or 4 mg transdermal. Sugimoto et al [START_REF] Sugimoto | Clinical evaluation of bisoprolol in the treatment of extrasystoles and sinus tachycardia: an interim report[END_REF] found more than 50% reduction of the PVC burden in 7 out of 16 patients on bisoprolol. Kobayashi et al [START_REF] Kobayashi | Dipyridamole suppresses catecholamine-and Ca++ influx-sensitive ventricular arrhythmias[END_REF] found that bisoprolol effectively inhibited PVC in 5 of 12 dipyridamole-respondent patients (reduction of 88 ± 16% of PVC) and in 3 of 6 dipyridamole-non-respondent patients. In their study, Shinohara et al [START_REF] Shinohara | Assessment of a novel transdermal selective beta1-blocker, the bisoprolol patch, for treating frequent premature ventricular contractions in patients without structural heart disease[END_REF] found that transdermal bisoprolol significantly reduced the PVC burden in the positive heart rate-PVC group, while the PVC burden did not change significantly in the non-positive heart rate-PVC group. In the positive heart rate dependent-PVC group, the patients with mean HRs > 80 bpm had a significantly higher percent improvement in the PVC count than those with mean HRs <80 bpm (p = 0.0080). However, all these 3 studies were performed on small populations of patients and therefore the results should be interpreted with caution.

Concerning patients with LQTS, there is weak evidence that bisoprolol might be both safe and efficient in the treatment of patients with this type of channelopathy. In their study on 34 patients with LQTS, Fazio et al found no major adverse cardiac event in patients treated with bisoprolol. Of the 12 minor cardiovascular events, 3 occurred in absence of treatment, 7 during treatment with nadolol or propranolol, and 2 during treatment with bisoprolol. The authors conclude that bisoprolol at doses of 0.1 -0.2 mg/kg might be less harmful and easier to manage than propranolol and nadolol [START_REF] Fazio | Role of bisoprolol in patients with long QT syndrome[END_REF]. In their study of 114 patients with LQTS, Steinberg et al [START_REF] Steinberg | Experience with bisoprolol in long-QT1 and long-QT2 syndrome[END_REF] observed QTc shortening in 59 subjects treated with bisoprolol (ΔQTc -5 ± 31 ms; p = 0.049). Bisoprolol was well tolerated during long-term administration (1 cardiac event = 1.7% during a 3-year follow-up). However, the authors conclude that the equivalence of bisoprolol for protection from ventricular arrhythmia in LQT patients compared to established beta-blockers remains unknown. Despite these promising results, due to the reduced number of studies on Bisoprolol in patients with LQTS, these data should be confirmed in larger clinical trials, before recommending bisoprolol as a safe and efficient beta blocker in this population of patients.

Overall, in patients with ventricular arrhythmias, bisoprolol reduces mortality and is efficient in reducing the number of hospitalizations due to severe arrhythmias in patients with stable heart failure. It lowers mortality and reduces the number of episodes of ventricular arrhythmias and MACE in patients with NSTEMI. It efficiently reduces the ventricular arrhythmia burden in patients with PVC. Its role in treating patients with LQTS is less well established.

Limitations of the study

The main limitation of this study is the heterogeneity of the studies included. The quality of the evidence is mixed, ranging from low quality to a few high quality studies, with the majority of the studies having a moderate quality. Few randomized clinical trials were found on this topic. With these heterogeneous data, a meta-analysis was impossible to conduct.

Conclusion

Current evidence exists supporting the use of Bisoprolol for the treatment of supraventricular arrhythmias, especially for rate control during atrial fibrillation. Evidence also exists for its efficacy in the treatment of ventricular arrhythmias, both in primary and in secondary prevention. Head to head clinical trials on large populations of patients comparing the safety and efficacy of Bisoprolol and other beta blockers are needed in order to better understand its rank among beta blockers for the treatment of arrhythmias.

Quali ty of evid ence

Neus s H et al (24) , 1986

Open label cohort -n=10 Paroxy smal SVT (of which 6 AVRT 2 AT 1 PAF) 10 mg iv In 5 of 6 patients with accessory AVpathways, circus movement tachycardia could be elicited prior to as well as after bisoprolol administration. In 1 of 2 patients with ectopic atrial tachycardia, bisoprolol prevented the induction of paroxysms.

In one patient with paroxysmal atrial fibrillation, the ventricular response decreased from 128/min to 94/min.

Mixed Low

Sugi moto T et al (25)

mg/day

The PAC frequency was decreased in 50% of the patients, and sinus tachycardia was improved in all 7 patients. Adverse reactions were observed in 8 of 32 patients.

Positi ve

Low Warg on M et al (73) , Two months after inclusion, heart rate decrease (baseline to 2 months) was 0.2 ± 13.7 bpm (placebo) and 9.8 ± 14.7 bpm (bisoprolol), p<0.0001. However, a benefit of bisoprolol on survival was obtained only in patients with sinus rhythm and was questionable in patients with atrial fibrillation.

Positi ve

High

J o u r n a l P r e -p r o o f rs) (74) , 2001

Bisop rolol) Katrit sis D et al (47) , J o u r n a l P r e -p r o o f

) (51) , 2013 double blind) beats/min, respectively, both p < 0.001), with a significant between-group difference (p = 0.033). Naka mura K et al (54) AF occurred in 24% of patients in the transdermal and in 46% of patients in the oral bisoprolol groups (p = 0.027). The use of transdermal bisoprolol was independently associated with a lower rate of AF (OR 0.21, 95% CI 0.05-0.84, p = 0.027). The incidence of post-operative AF in this group was lower than that in users of oral bisoprolol.

Positi ve

Mod erate Yasui T et al (44)

Figure 1 . 1 .Tableau 2 .

 112 Figure 1. Organigramme décrivant les étapes de sélection des références utilisées dans cette revue Tableau 1. Le rôle du bisoprolol dans le traitement des arythmies supraventriculaires -données des études cliniques. * -cette étude a inclus une population mixte de patients, certains avec SVT, d'autres avec PVC. Seul l'effet du bisoprolol sur les patients atteints de SVT est évalué ici. Pour la discussion sur cette étude sur l'efficacité du bisoprolol chez les patients atteints de PVC, veuillez consulter le tableau 2. FA = fibrillation auriculaire; AT = tachycardie atriale; AV = auriculo-ventriculaire; AVRT = tachycardie par réentrée auriculo-ventriculaire; AVNRT = tachycardie par réentrée intra-nodale; HF = insuffisance cardiaque; FC = fréquence cardiaque; PAC = extrasystoles supraventriculaires; P-AF = fibrillation auriculaire paroxystique; PVC = extrasystoles ventriculaires ; QOL = qualité de vie; SR = rythme sinusal; SVT = tachycardie supraventriculaire. Tableau 2. Le rôle du bisoprolol dans le traitement des arythmies ventriculaires -données des études cliniques. * -cette étude a inclus une population mixte de patients, certains avec SVT, d'autres avec PVC. Seul l'effet du bisoprolol sur les patients atteints de PVC est évalué ici. Pour la discussion sur cette étude sur l'efficacité du bisoprolol chez les patients atteints de SVT, veuillez consulter le tableau 1. HD = hémodynamique; HF = insuffisance cardiaque; FC = fréquence cardiaque; LQTS = syndrome du QT long; MACE = événements cardiaques indésirables majeurs; IM = infarctus du myocarde; NSTEMI = infarctus du myocarde sans élévation du segment ST; PVC = extrasystoles ventriculaires; ST = tachycardie sinusale; VA = arythmies ventriculaires; VF = fibrillation ventriculaire; TV = tachycardie ventriculaire.

Figure

  Figure 1

Total: 325 Total: 297 Total: 28 Table 1 Refer ence Type of study

  [START_REF] Quirke | Putting theory into practice: James Black, receptor theory and the development of the beta-blockers at ICI, 1958-1978[END_REF]

	Drug / interv	Patie nts (num	Search term Type Dose of of Bisoprol arrhyt ol	Excluded Findings 182	Concl Included usion on
	entio	ber)	arrhythmias hmia	(6 not in English	effica	9
	n comp		(n=191)	21 Case reports 2 studies on < 10 patients	cy (posit
	ared to			24 duplicates 127 not relevant 2 animal studies)	ive / negati ve / mixed
				70	)
				(9 not in English
			atrial fibrillation (n=84)	1 review 16 Case Reports 41 not relevant		14
				1 meta-analysis
				1 animal
				1 basic science study)
		premature ventricular	2
	Bisoprolol and		contractions	(1 case report		1
			(n=3)	1 not in English)
				29
		ventricular tachycardia	(1 not in English		2
			(n=31)	13 case reports 14 not relevant
				1 animal study)
				14
		ventricular fibrillation	(3 -case reports		1
			(n=15)	6 -not relevant 1 -full manuscript not
				available
				4 animal studies)
			manual search	0		1
			(n=1)

  Compared to landiolol 3 μg/kg/min, the introduction of the bisoprolol patch did not induce any significant changes in heart rate. There were no adverse events. effective for prophylaxis of AF after CABG (prevalence of AF of 12.7% vs 15.3%, p=0.60). Treatment with bisoprolol resulted in a trend to lower ventricular response rate in AF cases (125±6 beats/min vs 144±7 beats/min, p=.06). Both regimens are well tolerated. There was no difference between the 2 groups for the onset time of AF episodes, total AF duration, AF recurrence and postoperative length of hospital stay. Two reversible low cardiac output cases occurred with bisoprolol.

	Okam	Retros	trans	n=10	Atrial	2.5 mg
	ura H	pective	derm	8	Fibrilla	oral vs
	et al	cohort	al vs		tion	4 mg
	(43) ,	Open	Landi oral	n=16	Atrial (Post-	4 mg transder		Positi	Mod
	2019	label	olol admi		Fibrilla operati	mal		ve	erate
		retrosp	nistra		tion ve)
	,	ective	tion
	2016	cohort
	Yama	Multic	trans	n=22	Atrial	oral: 2.5	In Japanese patients with persistent or	Positi	Mod
	shita	enter	derm	0	Fibrilla	and 5 mg	permanent AF, transdermal 4 mg and 8 mg	ve	erate
	T et	double	al vs		tion	patch: 4	had heart rate reducing effects similar to
	al (53) ,	-blind	oral		(persis	mg and 8	those of oral bisoprolol 2.5 mg and 5 mg,
	2019	compa	admi		tent /	mg	respectively.
		rative	nistra		perma
		study	tion		nent)
	Behm	Open	usual	n=10	Atrial	5 mg /	The combination of bisoprolol plus Mg	Positi	Mod
	anes	label	care	0 (of	Fibrilla	day	effectively reduces the incidence of	ve	erate
	h S et	prospe		which	tion		postoperative AF following on-pump
	al ,	ctive		50	(proph		CABG, particularly in elderly patients, and
	2006	cohort		receiv	ylaxis		is associated with a shorter hospital length
				ed	after		of stay.
				bisop	CABG)		In the prophylaxis group, the incidence of
				rolol			postoperative AF was significantly lower,
				+			with 20% (10 / 50) compared to 42% (21 /
				Magn			50) among controls (p = 0.030, 95% CI for
				esium			absolute risk reduction = 2-42%).
				)
	Sleila ty G	Open label	Amio daron	n=20 0 (of	Atrial Fibrilla	2.5 mg bid	Postoperative amiodarone are equally Positi oral bisoprolol and ve	Mod erate
	et al	cohort	e	which	tion
	(40) ,			102	(proph
	2009			receiv	ylaxis
				ed	after
				Bisop	CABG)
				rolol)
	Mara	Open	Carve	n=32	Atrial	2.5 ± 0.2	Bisoprolol is more effective than carvedilol	Positi	Mod
	zzi G	label	dilol	0 (of	Fibrilla	mg	in decreasing the incidence of post-	ve	erate
	et al	prospe		which	tion		discharge AF after CABG in patients with
	(39) ,	ctive		160	(proph		decreased left ventricular function.
	2011	cohort		receiv	ylaxis		During follow-up, 23 patients (14.6%) in
				ed du	after		the bisoprolol group and 37 patients (23%)
				Bisop	CABG)		in the carvedilol group developed AF
				rolol)			(relative risk 0.6, confidence interval 0.4 to
							0.9, p < 0.032). After 4 weeks of treatment,
							patients in the bisoprolol group showed a
							significantly greater decrease in heart rate,
							being in sinus rhythm or AF (-15.6 ± 3 vs -
							9.4 ± 3 beats/min, p < 0.021).
	Sezai	Open	vs no	n=10	Atrial	2.5 mg /	Oral bisoprolol in combination with iv	Positi	Mod
	A et	label	thera	5 (of	Fibrilla	day	Landiolol is superior to iv landiolol and to	ve	erate
	al (42) ,	cohort	py vs	which	tion		no beta blocker therapy in the prevention
	2012		Landi	33	(proph		of post CABG AF.
			olol	receiv	ylaxis		Postoperative AF occurred in 14.5% of
				ed	after		group landiolol, 9.1% of group landiolol +
				Bisop	CABG)		bisoprolol, and 35.3% of group without
				rolol)			beta blockers.

J o u r n a l P r e -p r o o f

J o u r n a l P r e -p r o o f

Qualit y of evide nce

Sugimo to T et al (25) , 1986

Open label prospe ctive n=37 (of which 17 receiv ed Bisopr olol) PVC 2.5 mg/day More than 50% reduction of the PVC frequency was observed in 7 out of 16 patients on bisoprolol. The number of PVC was reduced in 2 out of 5 patients at a daily dose of 2.5 mg. Adverse reactions were observed in 8 of 32 patients.

Positi ve

Low Kobaya shi Y et al (69) , 1996

Open label prospe ctive n=12 PVC 5 mg/day Bisoprolol effectively inhibited PVC in 5 of 12 dipyridamole-respondent patients (reduction of 88 ± 16% of PVC) and in 3 of 6 dipyridamole-non-respondent patients.

Positi ve

Low Shinoha ra M et al (70) , The bisoprolol patch reduced the PVC count significantly in the positive HR-PVC group (P-PVC), while the PVC count did not change significantly in the non-positive HR-PVC group. In the P-PVC group, the patients with mean HRs > 80 bpm had a significantly higher percent improvement in the PVC count than those with mean HRs <80 bpm (p = 0.0080).

Positi ve

Mode rate Verrost te JM (75) , 1990

Open