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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 38-41

Observational study of new-onset atrial fibrillation in patients treated with Ivabradine alone versus Ivabradine and β-blocker drug (The BetaBrad Study)


Department of Cardiology, Lilavati Hospital and Research Centre (LHRC), Mumbai, Maharashtra, India

Date of Submission22-Feb-2022
Date of Acceptance03-Mar-2022
Date of Web Publication23-Mar-2022

Correspondence Address:
Dr. Rohan S Thanedar
Department of Cardiology, Lilavati Hospital and Research Centre (LHRC), Bandra West, Mumbai 400050, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_24_22

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  Abstract 

Introduction: Ivabradine is a heart rate lowering agent by inhibiting Iƒ current in sinus node. It is approved for use in patients with angina and heart failure for heart rate control. Recently, the concern has grown over increased incidence of atrial fibrillation in patients treated with Ivabradine. Aims: We observed critically ill patients in the intensive care unit, treated with Ivabradine alone versus Ivabradine plus a β-blocking agent, and compared the incidence of new-onset atrial fibrillation. Settings and Design: This was an observational, single-center study. Materials and Methods: We observed 40 patients who were divided into two groups. One group of patients was treated with Ivabradine (no other heart rate-controlling agent) and the other group was treated with Ivabradine plus a β-blocker drug. We studied the incidence of atrial fibrillation in an observation period of 7 days in the intensive care unit along with other patient characteristics. We used appropriate analytical protocol to compare the two groups. Statistical Analysis Used: Student’s unpaired t test and Fisher’s exact probability test were applied. The value of P < 0.05 was considered statistically significant. Results: Although one patient treated with Ivabradine (and no other rate/rhythm controlling drug) had new-onset atrial fibrillation, there was no statistically significant increase in the incidence of atrial fibrillation in critically ill patients (during the observation period) treated with Ivabradine versus Ivabradine plus β-blocker drug. Conclusion: Our preliminary research suggests the use of Ivabradine for heart rate control in critically ill patients is not associated with an increased incidence of new-onset atrial fibrillation. However, we recommend a further larger study on this subject.

Keywords: Atrial fibrillation, β-blocker, Ivabradine


How to cite this article:
Thanedar RS, Kudva S, Sanzgiri P, Reddy C. Observational study of new-onset atrial fibrillation in patients treated with Ivabradine alone versus Ivabradine and β-blocker drug (The BetaBrad Study). MGM J Med Sci 2022;9:38-41

How to cite this URL:
Thanedar RS, Kudva S, Sanzgiri P, Reddy C. Observational study of new-onset atrial fibrillation in patients treated with Ivabradine alone versus Ivabradine and β-blocker drug (The BetaBrad Study). MGM J Med Sci [serial online] 2022 [cited 2022 May 17];9:38-41. Available from: http://www.mgmjms.com/text.asp?2022/9/1/38/340585




  Key Messages: Top


Though Ivabradine has been a controversial drug, there is no significant rise in the incidence of atrial fibrillation in critically ill patients treated with Ivabradine alone compared to Ivabradine plus a β-blocker.


  Introduction Top


The action and role of Ivabradine in heart failure and angina is distinct and well accepted as it acts more distinctively than that of β-blockers and calcium channel blockers; it lowers heart rate without disturbing myocardial contractility or vascular tone.[1],[2],[3] On the contrary, β-blockers despite being preferred as the agent to control heart rate have their limitations. Especially in asthmatic and young populations.[4] It triggered the widespread use of Ivabradine as a rate control measure. However, concerns were raised when observations came in about Ivabradine’s role in triggering atrial tachyarrhythmias. Ivabradine inhibits the Iƒ current in the sinus node. However, it is observed that sudden sympathetic withdrawal triggers tachyarrhythmias, notedly atrial fibrillation, from ectopic atrial sites when the Iƒ current in the sinus node is in the inhibited state. This is attributed to excess norepinephrine and other neurohormonal mediators. Hence, it was important to examine Ivabradine actions in critically ill patients where the patients are most vulnerable to unstable or unbalanced sympathetic and parasympathetic activity.

There are various opinions and conclusions regarding Ivabradine’s vast actions and interactions, and limited understanding of implications of Ivabradine’s use in scenarios ranging from triggering atrial fibrillation to rate control in tachyarrhythmias. Hence, we observed critically ill patients in the intensive care unit, treated with Ivabradine alone versus Ivabradine plus a β-blocking agent, and compared the incidence of new-onset atrial fibrillation.


  Materials and methods Top


This was an observational, single-center study that included 40 critically ill patients who were admitted to the intensive care unit of a tertiary care hospital in India between January 2019 and June 2019. The patients were divided into two groups according to the drugs used for treatment: one group consisted of patients treated with Ivabradine alone for heart rate control and the other group consisted of patients treated with Ivabradine plus β-blocker. As this was a purely observational study, initiation, dosage, and/or withdrawal of any drug was not controlled by investigators. Patients who could fulfill the criteria of seven days observation in the intensive care unit while being on either Ivabradine alone or Ivabradine plus β-blocker were only included in the study. The incidence of atrial fibrillation in both groups during seven days observation period was compared. The group of this study which included patients treated with Ivabradine only is referred to as Group A, whereas the group which included patients treated with both Ivabradine plus a β-blocker is referred to as Group B. Statistical analysis was done by an independent biostatistician. The statistical analysis was done using the Statistical Package for Social Sciences software program, version 16.0 (SPSS, Chicago, Illinois). Continuous variables are presented as mean and standard deviation. Categorical variables are expressed as frequency and percentage. The Student’s unpaired t test and Fisher’s exact probability test were applied. The value of P < 0.05 was considered statistically significant.


  Results Top


The mean age of subjects in Group A (Ivabradine only) was 60.5 years, whereas in Group B (Ivabradine plus β-blocker) it was 58.9 years. One patient in Group A had valvular heart disease and two had LA enlargement. The number of diabetic and hypertensive patients in both groups was comparable. In Group A, 9 (out of 20) patients had ischemic heart disease (IHD), whereas in Group B 7 (out of 20) patients had IHD. Five patients in Group A and seven patients in Group B had overt heart failure. Four patients in Group A and five patients in Group B had left ventricle dysfunction (LVEF <40%). Two patients in Group A and one patient in Group B had undergone noncardiac surgery just before enrollment in this study. There were no patients who were survivors of cardiac arrest, who had right ventricle dysfunction, right atrium enlargement, or pericarditis/pericardial effusion in both groups. Detailed demographics are represented in [Table 1].
Table 1: Baseline parameters of the patients

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One patient in Group A had atrial fibrillation during the study who needed treatment intervention with intensive care unit stay of more than 10 days and the same patient died during his hospital stay. There was no case of new-onset atrial fibrillation in Group B. However, we could not prove this difference statistically significant [Table 2].
Table 2: Outcomes of the treatment

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  Discussion Top


The studies about myriad actions and effects of Ivabradine are rare. A meta-analysis of three trials, BEAUTIFUL, SHIFT, and SIGNIFY by Mengesha et al.[5] reported that Ivabradine significantly increased the incidence of symptomatic bradycardia and atrial fibrillation compared to placebo and suggested cautious and just use of Ivabradine. Martin et al.[6] in their meta-analysis stated that the use of Ivabradine was related to approximately 15% intensification in the risk of developing atrial fibrillation. They also postulated the possible role of HCN4 and Iƒ current inhibition in the genesis of atrial fibrillation. Iliuta et al.[7] in their meta-analysis noted that in-hospital postoperative AF or tachyarrhythmias were less common with combined therapy of metoprolol and Ivabradine than with either drug alone. The associated relative risk showed a better protective value against the occurrence of postoperative AF in patients undertaking cardiac surgery interventions treated with a combination of drugs compared with metoprolol only. The patients who were administered Ivabradine were found to improve the QOL, had to stay for a lesser duration in hospital, and reduced the duration of immobilization in the postoperative period. The occurrence of supraventricular or ventricular arrhythmias was also reduced.

In an entirely different perspective about Ivabradine’s actions, Turley et al.[8] in their article regarding the emerging role of Ivabradine in atrial fibrillation concluded that Ivabradine could decrease conduction through the AV node, and act towards the decrease in heart rate without any hemodynamic complications in patients with AF. This aspect was supported by an editorial by Caminiti et al.[9] which stated that Ivabradine had the potential to be a promising rate-control agent in patients with non-paroxysmal AF, particularly in elderly frail patients. Its amalgamation with other heart rate lowering drugs, particularly with β-blockers, can be remarkably attractive because the combination therapy could achieve an advisable heart rate in the majority of patients with non-paroxysmal AF compared to β-blockers alone. Moreover, in frail elderly patients, the blend of low doses of two drugs might be better tolerated than high doses of β-blockers.

Although our study failed to identify statistical significance in two groups, it is important to note one patient in Group A had atrial fibrillation and eventually died in hospital. This cannot be solely attributed to any drug as other confounding factors could have potentially led to the outcome of that patient. The addition of β-blocker to Ivabradine may partially mitigate the risk of neurohormonal mediated stimulation of tachyarrhythmias including atrial fibrillation. Both Ivabradine and β-blocker drugs given together may help to reduce the dose of the individual drug and achieve rate control earlier. However, serious bradycardia and other side effects should be carefully looked for and treated accordingly.

The limitations of this study are that it is an observational study, and the number of patients included in this study was less and did not power this study to reach a definite conclusion.


  Conclusion Top


There is no significant rise in the incidence of atrial fibrillation in critically ill patients treated with Ivabradine alone compared to Ivabradine plus a β-blocker. Further research with a large number of patients is needed on the same subject.

Ethical policy and institutional review board statement

Institutional Ethics Committee, Lilavati Hospital, and Research Centre, Mumbai, Maharashtra, India have approved in its Research Advisory Committee meeting held on December 18, 2018 for undertaking the study on “Observational study of new-onset atrial fibrillation in patients treated with Ivabradine alone versus Ivabradine and β-blocker drug (The BetaBrad Study)” vide letter dated January 16, 2019. The decision was also taken in the meeting to grant an informed consent waiver.

Financial support and sponsorship

Nil.

Conflict of interest

There are no conflicts of interest.



 
  References Top

1.
Chen C, Kaur G, Mehta PK, Morrone D, Godoy LC, Bangalore S, et al. Ivabradine in cardiovascular disease management revisited: A review. Cardiovasc Drugs Ther 2021;35:1045-56.  Back to cited text no. 1
    
2.
Tse S, Mazzola N Ivabradine (corlanor) for heart failure: The first selective and specific I f inhibitor. P T 2015;40:810-4.  Back to cited text no. 2
    
3.
Koruth JS, Lala A, Pinney S, Reddy VY, Dukkipati SR The clinical use of Ivabradine. J Am Coll Cardiol 2017;70:1777-84.  Back to cited text no. 3
    
4.
Morales DR, Guthrie B, Lipworth BJ, Donnan PT, Jackson C Prescribing of β-adrenoceptor antagonists in asthma: An observational study. Thorax 2011;66:502-7.  Back to cited text no. 4
    
5.
Mengesha HG, Weldearegawi B, Petrucka P, Bekele T, Otieno MG, Hailu A Effect of Ivabradine on cardiovascular outcomes in patients with stable angina: Meta-analysis of randomized clinical trials. BMC Cardiovasc Disord 2017;17:105.  Back to cited text no. 5
    
6.
Martin RI, Pogoryelova O, Koref MS, Bourke JP, Teare MD, Keavney BD Atrial fibrillation associated with Ivabradine treatment: Meta-analysis of randomised controlled trials. Heart 2014;100:1506-10.  Back to cited text no. 6
    
7.
Iliuta L, Rac-Albu M Ivabradine versus beta-blockers in patients with conduction abnormalities or left ventricular dysfunction undergoing cardiac surgery. Cardiol Ther 2014;3:13-26.  Back to cited text no. 7
    
8.
Turley SL, Francis KE, Lowe DK, Cahoon WD Jr. Emerging role of Ivabradine for rate control in atrial fibrillation. Ther Adv Cardiovasc Dis 2016;10:348-52.  Back to cited text no. 8
    
9.
Caminiti G, Cacciapuoti F, Fossati C, Battaglia D, Punzo N, Volterrani M Heart rate control in non-paroxysmal atrial fibrillation: A new indication for Ivabradine? J Cardiol Ther 2017;4:671-5.  Back to cited text no. 9
    



 
 
    Tables

  [Table 1], [Table 2]



 

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