SUMMARY

BACKGROUND/INTRODUCTION:

Heart failure patients with reduced ejection fraction are at high risk for ventricular arrhythmias and sudden cardiac death. Ivabradine, a specific inhibitor of the I_f current in the sinoatrial node, provides heart rate reduction in sinus rhythm and angina control in chronic coronary syndromes.

OBJECTIVE:

The effect of ivabradine on ventricular arrhythmias in heart failure patients with reduced ejection fraction patients has not been fully elucidated. The aim of this study was to investigate the effect of ivabradine use on life-threatening arrhythmias and long-term mortality in heart failure patients with reduced ejection fraction patients.

METHODS:

In this retrospective study, 1,639 patients with heart failure patients with reduced ejection fraction were included. Patients were divided into two groups: ivabradine users and nonusers. Patients presenting with ventricular tachycardia, the presence of ventricular extrasystole, and ventricular tachycardia in 24-h rhythm monitoring, appropriate implantable cardioverter-defibrillator shocks, and long-term mortality outcomes were evaluated according to ivabradine use.

RESULTS:

After adjustment for all possible variables, admission with ventricular tachycardia was three times higher in ivabradine nonusers (95% confidence interval 1.5–10.2). The presence of premature ventricular contractions and ventricular tachycardias in 24-h rhythm Holter monitoring was notably higher in ivabradine nonusers. According to the adjusted model for all variables, 4.1 times more appropriate implantable cardioverter-defibrillator shocks were observed in the ivabradine nonusers than the users (95%CI 1.8–9.6). Long-term mortality did not differ between these groups after adjustment for all covariates.

CONCLUSION:

The use of ivabradine reduced the appropriate implantable cardioverter-defibrillator discharge in heart failure patients with reduced ejection fraction patients. Ivabradine has potential in the treatment of ventricular arrhythmias in heart failure patients with reduced ejection fraction patients.

KEYWORDS:
Ivabradine; Mortality; Implantable cardioverter defibrillator; Cardiac arrhythmia; Heart failure

INTRODUCTION

Heart failure (HF) patients, especially those with HF with reduced ejection fraction (HFrEF), are at high risk for ventricular arrhythmias and sudden cardiac death. Both implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy with an ICD (CRT-D) have been shown to successfully treat life-threatening ventricular arrhythmias and to reduce cardiac mortality in patients with HFrEF¹1 Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225-37. https://doi.org/10.1056/NEJMoa043399
https://doi.org/10.1056/NEJMoa043399... ,²2 Circulation. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Circulation. 1997;95(4):777. https://doi.org/10.1161/01.cir.95.4.777
https://doi.org/10.1161/01.cir.95.4.777... . Traditionally, patients with HFrEF who survive from life-threatening ventricular arrhythmias are at increased risk for recurrent lethal arrhythmias in the long-term follow-up. In addition, detection of ventricular arrhythmia in such patients has been reported to be a poor prognostic predictor³3 Carson P, Anand I, O'Connor C, Jaski B, Steinberg J, Lwin A, et al. Mode of death in advanced heart failure: the comparison of medical, pacing, and defibrillation therapies in heart failure (COMPANION) trial. J Am Coll Cardiol. 2005;46(12):2329-34. https://doi.org/10.1016/j.jacc.2005.09.016
https://doi.org/10.1016/j.jacc.2005.09.0... .

Ivabradine, a specific inhibitor of the I_f current in the sinoatrial node, provides a pure heart rate reduction in patients with sinus rhythm⁴4 Francesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757-65. https://doi.org/10.2165/00003495-200464160-00003
https://doi.org/10.2165/00003495-2004641... . Ivabradine is currently recommended to treat patients with stable angina, HF, as well as inappropriate sinus tachycardia⁵5 Borer JS, Fox K, Jaillon P, Lerebours G, Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107(6):817-23. https://doi.org/10.1161/01.cir.0000048143.25023.87
https://doi.org/10.1161/01.cir.000004814... –⁷7 Kumar S, Vohra J. Ivabradine: appropriate treatment for inappropriate sinus tachycardia. Heart Rhythm. 2010;7(9):1324-5. https://doi.org/10.1016/j.hrthm.2010.06.012
https://doi.org/10.1016/j.hrthm.2010.06.... . Outcomes of randomized trial on chronic heart failure demonstrated that ivabradine improved the long-term survival and reduced the rate of hospitalization in patients with HFrEF⁶6 Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-85. https://doi.org/10.1016/S0140-6736(10)61198-1
https://doi.org/10.1016/S0140-6736(10)61... . However, in this study, ventricular arrhythmias were not monitored, and patients with high ventricular arrhythmia burdens were excluded from the trial. Therefore, the effects of ivabradine on ventricular arrhythmias in HFrEF patients have not been fully elucidated. Thus, in this study, we aimed to investigate the effect of ivabradine on life-threatening arrhythmias and long-term mortality in HFrEF patients.

METHODS

Data collection

In this retrospective study, we reviewed all patients with HFrEF who were admitted to our center between January 2010 and April 2021. The diagnosis of HFrEF was made based on the ICD codes in the hospital electronic database system and a previous transthoracic echocardiographic report demonstrating a left ventricle ejection fraction (LVEF) of ≤40%. In all, 1,639 HFrEF patients were evaluated in this investigation. The electronic database at our institution was employed to gather baseline information, laboratory results, and echocardiographic data. All patients received guideline-directed medical therapy for HFrEF. Transthoracic echocardiography was performed on all patients by a cardiovascular imaging specialist using the Vivid 7 (GE Vingmed Ultrasound AS, Horten, Norway) system. The LVEF was measured using the modified Simpson's method, and left ventricular end-diastolic and end-systolic volumes were evaluated on apical two- and four-chamber views. In addition, patients whose echocardiographic data could not be evaluated accurately and under the age of 18 years were excluded from the study. A 24-h rhythm Holter monitoring was performed in patients with palpitations, presyncope, and unexplained syncope complaints. For the presence of premature ventricular contractions (PVCs), the arrhythmia burden limit was determined to be >10% in 24-h rhythm Holter monitoring⁸8 Latchamsetty R, Bogun F. Premature ventricular complex-induced cardiomyopathy. JACC Clin Electrophysiol. 2019;5(5):537-50. https://doi.org/10.1016/j.jacep.2019.03.013
https://doi.org/10.1016/j.jacep.2019.03.... . In HFrEF patients who were implanted with ICD or CRT-D, device therapy, such as anti-tachycardia pacing or shock, delivered in response to ventricular tachycardia (VT) or ventricular fibrillation (VF), was considered an appropriate therapy. Inappropriate device therapy was defined as any therapy given in reaction to atrial fibrillation, supraventricular tachycardia, sinus tachycardia, or device malfunction. Data on device therapy were acquired from patients’ records and, where applicable, verified with device interrogation records. The regular use of ivabradine was confirmed by the data of the Ministry of Health since ivabradine is required to be used based on the medical reports according to the rules of the current insurance system.

Study outcomes

The primary endpoints of this investigation were long-term all-cause mortality and the occurrence of ventricular tachycardia, the presence of PVC burden >10% on 24-h Holter monitoring, the presence of ventricular tachycardia on 24-h Holter monitoring, and proper ICD shock. The long-term survival status of each patient was determined using the National Death Notification System.

Statistical analysis

The statistical analysis was performed using the Statistical Package for Social Sciences 20.0 software (IBM SPSS 20, SPSS Inc., Chicago, Illinois, USA). The study population was divided into two groups according to patients’ ivabradine use: patients not using ivabradine (n=1363), and patients using ivabradine (n=276). The demographic features and clinical characteristics of the study groups were compared. Kolmogorov-Smirnov test was used for the evaluation of normality. Continuous variables were presented as median and interquartile range or mean and standard deviation compared using the t-test or the Mann-Whitney U test, as appropriate. A p<0.05 was considered statistically significant. Categorical variables were presented as numbers and percentages. Analyses of categorical variables were performed by Pearson's chi-square test or the Fisher's exact test. Cox regression models were formed in order to elucidate the effect of ivabradine use on the outcomes. The results of regression analysis were presented as a hazard ratio (HR) with a 95% confidence interval (CI). Two models were used in the Cox regression analysis: model I, unadjusted, and model II, adjusted. Model II was adjusted to baseline demographics and risk factors for admissions, serving as a reference group. The variables co-variated in the model II were age, gender, hypertension, diabetes mellitus, smoking, hyperlipidemia, chronic obstructive pulmonary disease, coronary artery disease, chronic renal failure, HF etiology, LVEF, beta-blockers, angiotensinogen-converting enzyme inhibitors or angiotensinogen receptor blockers, spironolactone, and furosemide.

RESULTS

A total of 1,639 patients with HFrEF [median age: 71 (63–79) years and 946 (57.7%) were males] were included in the study. In total, 276 patients were in the ivabradine group. In terms of baseline features, 1086 (66.3%) patients had ischemic HFrEF, while 553 patients (33.7%) had nonischemic HFrEF. In regard to device therapy, 281 patients had ICD implantation and 105 patients had CRT-D implantation. The mean LVEF was 30% (25.0–35.0). The study population included 91 patients using ivabradine and implanted ICDs, compared to 295 patients with ICDs not using ivabradine. Baseline clinical features are summarized in Table 1.

In terms of arrhythmias, 44 patients who presented with VT on admission were not treated with ivabradine, while 4 patients who developed VT on admission were treated with ivabradine (Table 2). PVCs were observed in 24-h rhythm Holter monitoring in 169 (36.2%) non-ivabradine users, while they were observed in 64 (21.7%) ivabradine users. While VT was detected in 12 (2.6%) patients not using ivabradine in 24-h rhythm Holter monitoring applied to patients, it was detected in 2 (0.7%) patients using ivabradine. The frequency of ICD discharge was significantly higher in patients who were not treated with ivabradine compared with those who were treated (n=64 vs. n=7), respectively. Finally, long-term mortality was observed in 143 (10.5%) non-ivabradine users, while it was observed in 22 (8%) ivabradine users.

According to the model adjusted for all covariates, the risk of VT on admission was observed three times more in non-ivabradine users than in users (Table 3). There was no significant difference between the two groups in terms of long-term mortality. According to the adjusted model for all variables, the presence of PVCs in 24-h rhythm Holter monitoring was 2.4 times higher in patients not using ivabradine than in those using it. All variable-adjusted analyses showed 4.2 times more VT on 24-h rhythm Holter monitoring in non-ivabradine users than in ivabradine users. According to the model adjusted for all variables, approximately 4.1 times more ICD discharges were observed in the group that did not use ivabradine than in the group that used it.

DISCUSSION

The current study has shown that ivabradine reduces appropriate ICD therapy in HFrEF patients. Additionally, the use of ivabradine significantly reduced VT on admission, the presence of PVCs, and VT detection in 24-h rhythm Holter monitoring in HFrEF patients.

The I_f channel, which is one of the most important ionic currents regulating the pacemaker activity in the sinoatrial (SA) node, is a mixed Na–K inward current activated by hyperpolarization. Ivabradine exerts this effect without prolonging QTc or altering conductance, refractoriness, or repolarization time of the atria, atria-ventricle (AV) node, His-Purkinje system, and ventricles⁹9 Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs R D. 2003;4(2):83-9. https://doi.org/10.2165/00126839-200304020-00001
https://doi.org/10.2165/00126839-2003040... . It prolongs diastole by decreasing the diastolic depolarization slope in SA node cells¹⁰10 Thollon C, Cambarrat C, Vian J, Prost JF, Peglion JL, Vilaine JP. Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49. Br J Pharmacol. 1994;112(1):37-42. https://doi.org/10.1111/j.1476-5381.1994.tb13025.x
https://doi.org/10.1111/j.1476-5381.1994... . As a result, by prolonging diastole time, it reduces myocardial oxygen demand and increases myocardial perfusion. Heart rate plays an important role in the pathophysiology of HF, and ivabradine-induced heart rate reduction improves clinical outcomes in selected patient groups⁶6 Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-85. https://doi.org/10.1016/S0140-6736(10)61198-1
https://doi.org/10.1016/S0140-6736(10)61... . With the use of ivabradine in our patients, heart rate reduction may have improved myocardial perfusion by prolonging diastole and may have prevented ventricular arrhythmias by reducing Ischemia.

The cyclic nucleotide-gated channel 4 current (HCN4), the primary site of action of ivabradine, is highly expressed in the SA node. It is expressed at a low level in normal ventricular myocytes, whereas the expression of HCN channels is increased in ventricular myocytes in HF. I_f currents may be responsible for the abnormal automaticity in the ventricles in HF, and ivabradine may prevent ventricular arrhythmias by blocking the HCN channel¹¹11 Oknińska M, Paterek A, Zambrowska Z, Mackiewicz U, Mączewski M. Effect of ivabradine on cardiac ventricular arrhythmias: friend or foe? J Clin Med. 2021;10(20):4732. https://doi.org/10.3390/jcm10204732
https://doi.org/10.3390/jcm10204732... . This increased HCN channel expression observed in the ventricles of HF patients may underlie the possible anti-arrhythmic effect of ivabradine observed in our patients.

Ivabradine has also been shown to inhibit I_f channels, which are normally found only in the SA node but pathologically expressed in the ventricular myocardium with HF¹²12 Musiałek P. If current inhibition and mortality reduction in heart failure: more than just a ‘pure’ effect of lowering heart rate. Kardiol Pol. 2013;71(7):764-7. https://doi.org/10.5603/KP.2013.0168
https://doi.org/10.5603/KP.2013.0168... . Heart rate during Ischemia is associated with reperfusion arrhythmias, and a lower heart rate during Ischemia delays Ischemia-induced electrophysiological changes¹³13 Cerbai E, Pino R, Porciatti F, Sani G, Toscano M, Maccherini M, et al. Characterization of the hyperpolarization-activated current, I(f), in ventricular myocytes from human failing heart. Circulation. 1997;95(3):568-71. https://doi.org/10.1161/01.cir.95.3.568
https://doi.org/10.1161/01.cir.95.3.568... . It has been shown that I_f current activity increases the pro-arrhythmogenic potential as a result of prolongation of the ventricular repolarization phase¹⁴14 Hofmann F, Fabritz L, Stieber J, Schmitt J, Kirchhof P, Ludwig A, et al. Ventricular HCN channels decrease the repolarization reserve in the hypertrophic heart. Cardiovasc Res. 2012;95(3):317-26. https://doi.org/10.1093/cvr/cvs184
https://doi.org/10.1093/cvr/cvs184... . In conclusion, I_f channel blockers suggest a potential approach to prevent sudden death in HFrEF patients. There is a case report where ivabradine was used in addition to antiarrhythmic drugs and catheter ablation in patients with resistant ventricular arrhythmia¹⁵15 Çinier G, Hayıroğlu Mİ, Özcan KS, Pay L, Tekkeşin Aİ, Gürkan K. The use of ivabradine in a patient with idiopathic ventricular arrhythmia originating from the left ventricular summit. J Electrocardiol. 2022;71:32-6. https://doi.org/10.1016/j.jelectrocard.2021.12.010
https://doi.org/10.1016/j.jelectrocard.2... .

The exact mechanisms of ivabradine's efficacy in the treatment of tachycardias originating from outside the sinus node and due to enhanced automaticity are not yet known. The first possible mechanism is that it inhibits increased automaticity as a result of increased expression of HCN channels in ventricular myocytes. There are case reports suggesting that ivabradine may have potential in the pediatric population for the treatment of a variety of atrial tachycardias in which increased automaticity is considered the primary underlying mechanism¹⁶16 Bohora S, Lokhandwala Y, Parekh P, Vasavda A. Reversal of tachycardiomyopathy due to left atrial tachycardia by ivabradine. J Cardiovasc Electrophysiol. 2011;22(3):340-2. https://doi.org/10.1111/j.1540-8167.2010.01860.x
https://doi.org/10.1111/j.1540-8167.2010... ,¹⁷17 Kumar V, Kumar G, Tiwari N, Joshi S, Sharma V, Ramamurthy R. Ivabradine as an Adjunct for refractory junctional ectopic tachycardia following pediatric cardiac surgery: a preliminary study. World J Pediatr Congenit Heart Surg. 2019;10(6):709-14. https://doi.org/10.1177/2150135119876600
https://doi.org/10.1177/2150135119876600... . The possible anti-arrhythmic effect of ivabradine can be considered as a result of suppressing automaticity, reducing PVC burden, and preventing VT trigger. The second possible explanation is that ivabradine prevents triggered activity-mediated arrhythmias induced by prolonging ventricular repolarization by its inhibiting effect on hERG channels¹⁸18 Melgari D, Brack KE, Zhang C, Zhang Y, Harchi A, Mitcheson JS, et al. hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine. J Am Heart Assoc. 2015;4(4):e001813. https://doi.org/10.1161/JAHA.115.001813
https://doi.org/10.1161/JAHA.115.001813... .

There are various case reports in the literature regarding the suppression of ventricular arrhythmias. In a study of mice with cardiomyopathy, ivabradine was shown to suppress early PVCs, sustain ventricular arrhythmias, and improve survival¹⁹19 Kuwabara Y, Kuwahara K, Takano M, Kinoshita H, Arai Y, Yasuno S, et al. Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts. J Am Heart Assoc. 2013;2(3):e000150. https://doi.org/10.1161/JAHA.113.000150
https://doi.org/10.1161/JAHA.113.000150... . Experimental studies suggest that the antiarrhythmic effects of ivabradine are due to the following mechanisms: [1] it conserves energy by reducing heart rate and prevents electrophysiological effects of Ischemia and [2] it blocks HCN channels that are overexpressed in the ventricles in HF¹¹11 Oknińska M, Paterek A, Zambrowska Z, Mackiewicz U, Mączewski M. Effect of ivabradine on cardiac ventricular arrhythmias: friend or foe? J Clin Med. 2021;10(20):4732. https://doi.org/10.3390/jcm10204732
https://doi.org/10.3390/jcm10204732... .

All these studies show that ivabradine reduces ventricular arrhythmias in HF patients and support our current study results. In our HFrEF patient group, ivabradine may have reduced the ventricular arrhythmias by the abovementioned possible mechanisms. The presence of PVC, appropriate ICD shocks, and ventricular arrhythmias in HFrEF patients is associated with high mortality²⁰20 Le VV, Mitiku T, Hadley D, Myers J, Froelicher VF. Rest premature ventricular contractions on routine ECG and prognosis in heart failure patients. Ann Noninvasive Electrocardiol. 2010;15(1):56-62. https://doi.org/10.1111/j.1542-474X.2009.00340.x
https://doi.org/10.1111/j.1542-474X.2009... –²²22 Saxon LA, Bristow MR, Boehmer J, Krueger S, Kass DA, Marco T, et al. Predictors of sudden cardiac death and appropriate shock in the comparison of medical therapy, pacing, and defibrillation in heart failure (COMPANION) trial. Circulation. 2006;114(25):2766-72. https://doi.org/10.1161/CIRCULATIONAHA.106.642892
https://doi.org/10.1161/CIRCULATIONAHA.1... . In the present study, we showed that ivabradine reduces ventricular arrhythmias in HFrEF patients. However, no statistically significant reduction in total mortality was demonstrated. The reason for the statistical insignificance may be that HFrEF patients in our population died because of pump failure. Prospective studies with larger patient populations are needed to demonstrate the effects of ivabradine more clearly on ventricular arrhythmias.

Our study has several limitations. First, our study had a single-center, retrospective design. Second, the optimization of medical treatment for all patients in the follow-up period is unknown. Third, all patients could not be evaluated with 24-h rhythm Holter monitoring. Unfortunately, 24-h rhythm Holter monitoring was applied only to patients with symptoms. Fourth, the optimal medical treatment of patients did not include SGLT-2 inhibitors, which might have affected the results. Finally, the brain natriuretic peptide levels of all patients were not routinely checked during hospitalizations.

CONCLUSION

The use of ivabradine has been shown to reduce appropriate ICD therapy in patients with HFrEF. The use of ivabradine in HFrEF patients may have potential for preventing ventricular arrhythmias.

REFERENCES

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