IMPACT OF SACUBITRIL/VALSARTAN COMBINATION ON PREVALENCE OF ARRHYTHMIA IN HEART FAILURE PATIENTS WITH REDUCED EJECTION FRACTION

IMPACT OF SACUBITRIL/VALSARTAN COMBINATION ON PREVALENCE OF ARRHYTHMIA IN HEART FAILURE PATIENTS WITH REDUCED EJECTION FRACTION

By

Hassan Shehata, Hayam El-Damnahoury, Ahmed M. Abd El-Samee and Lamyaa Allam

Cardiology Department, Ain Shams Faculty of Medicine

Author: Hassan shehata; E-mail: shehatahassan0@gmail.com; Phone: +02 01028202718

ABSTRACT

Background: In the PARADIGM-HF trial, Heart failure with reduced ejection fraction (HFrEF) patients on (sacubitril/valsartan) had a substantially lower rate of hospitalization for HF and mortality compared to Enalapril. Only very few data exist regarding the impact of sacubitril/valsartan on arrhythmia in those patients.

Objective: To assess the effect of Sacubitril/Valsartan combination on prevalence of arrhythmias in HFrEF patients and compare it with patients on Angiotensin converting enzyme inhibitor (ACEI) or Angiotensin receptors blockers (ARBs).

Patients and Methods: Sixty patients with heart failure with reduced ejection fraction were classified into: Group A on Sacubitril\Valsartan combination therapy, and group B on ACEI or ARBs for at least 3 months with follow up as regard the burden of arrhythmia by 48 hours holter monitoring at 3 and 6 months.

Results: There was no significant difference in both groups as regard demographic and medical data Group A was characterized by significant decrease in ventricular ectopics and significant improvement in ejection fraction (EF), Left ventricular internal dimension (lVIDd) and right ventricular systolic pressure (RVSP) (p=0.00) in comparison to group B.

Conclusion: Sacubitril/Valsartan combination therapy was superior to ACEIs or ARBs in reducing ventricular ectiopic as a mechanism for preventing of sudden cardic death (SCD).

Keywords: HFrEF, ACEI, ARBs-SCD, Left atrium, LVIDd, RVSP.

INTRODUCTION

     The treatment of chronic heart failure with reduced LVEF (HFrEF) using angiotensin- converting enzyme (ACEI) inhibitors is well established, with angiotensin receptor blockers (ARBs) as a safe and proven alternative (Europian society of cardiology guidelines 2012& 2016). New therapeutic class of agents acting on the renin angiotensin aldosterone system (RAAS) and neutral endopeptidase system has been developed, known as angiotensin receptor neprilysin inhibitors (ARNI) (McMurray et al., 2014). In the PARADIGM-HF trial, HFrEF patients on (sacubitril/valsartan) had a substantially lower rate of hospitalization for HF and mortality compared to Enalapril (King et al., 2015).

     A subanalysis of the PARADIGM-HF trial also showed a reduction in sudden cardiac death by 20% in relation to Enalapril, which does not differ among patients with or without an implantable cardioverter defibrillator (ICD) (Mangiafico and Costello-Boerrigter 2013). Several potential mechanisms have been linked to this antiarrhythmic effect. Whether this reduction is caused by reverse remodeling, the reduction in myocardial fibrosis, wall stretch or sympathetic nervous system activation is not fully understood (de Diego and Gonzalez-Torres 2018 and Martens and Nuyens, 2019).

     The authors in this study assess the effect of valsartan \ sacubitril combination on incidence of arrhythmias in HFrEF patients in comparison to patients on ACEI or ARBs only.

Study population: This study was conducted at Ain Shams university and Nasr city insurance hospitals including 60 patients with  heart failure patients with reduced ejection fraction less than 40% either ischemic (proved by history, metabolic imaging or coronary angiography) or dilated. This was on either Sacubitril\Valsartan combination therapy or on ACEI or ARBs for at least 3 months. Patients with renal impairment, hyperkalemia, pace maker or CRT were excluded.

Ethics approval and informed consent:

     The study protocol was approved by Ain Shams Faculty of Medicine scientific and ethical committee. Data confidentiality and privacy were maintained. All patients were informed about the registry and written consent were taken.

PATIENTS AND METHODS

     This was an observational prospective study with random sampling of patients with collection of full data including medical histoty, ECG, echocardiography and laboratory data. Follow up the patients at 3, 6 months after initiation of Valsartan\ Sacubitril combination therapy, or ACEIs (ARBs) at maximum tolerated dose by up titration of the dose according to the tolerance of patients after assessment of blood pressure and also guided by blood investigations including serum creatinine and potassium level. The follow up included the medical status, compliance, ECG, echocardiography, laboratory investigation and holter monitoring.

Statistical analysis: Using computer software statistical package for the social sciences (SPSS, version 20, SPSS Inc., Chicago, Illinois, USA) Description of quantitative (numerical) variables was performed in the form of mean ± SD. Description of qualitative (categorical) data was performed in the form of number of cases and percent. Appropriate test of associations was performed using Chi-square test, Paired t-test, Wilcoxon signed-rank test, repeated measure ANOVA test and Friedman test the significance level was set at p-value of less than 0.05.

RESULTS

     The number of samples that fulfilled the inclusion and exclusion criteria in this study were 60 patients that were classified into 2 groups: 30 patients on Sacubitril\Valsartan combination therapy (group A), and 30 patients on ACEIs or ARBs (group B).

     There was no significant difference in demographic and clinical data of both groups (Table 1).

Table (1):   Demographic and clinical data of patients

     Through six months of follow up, Group A was characterized by non-significant reduction in QRS width and non-significant shortening in QTc while Group B was associated with non-significant increasing QTc values through the follow up period (Tables 2 & 3).

Table (2):   ECG changes in group A through the follow up period

Table (3):   ECG changes in group B through the follow up period

     Through six months of follow up, group A show significant improvement in EF (P= <0.001), RVSP (P= <0.001) and SWMA (P=0.005) with maximal improvement after 6 months While LA diameter increased after 3 month then declined again after the 6 month (p=0.02) while in group B Mean left atrium diameter was found to be increasing through the follow up period with highest values after six months. And RVSP was found to be improving through the follow up period with lowest values after six months (Tables 4, 5, 6 & 7).

Table (4):   Echocardiography changes in group A through the follow up period

Table (5):Post Hoc analysis of significant echocardiography changes in group A through the follow up period

Table (6):   Echocardiography changes in group B through the follow up period

Table (7):   Post Hoc analysis of significant echocardiography changes in group B through  the follow up period

     There was no significant difference through the follow up period in group A populations regarding serum creatinine and potassium level  while significant elevation in serum creatinine in group B (p=0.001) (Tables 8, 9 &10).

Table (8):   Kidney function and serum potassium changes in group A and B through the follow up period

Table (9):   Kidney function and serum potassium changes in group B through the follow up period

Table (10): Post Hoc analysis of significant kidney function in group B through the follow up period

     There was no significant difference through the follow up period in group A populations regarding clinical data while one mortality was in group B (tables 11& 12).

Table (11): Clinical data of group A through the follow up period

Table (12): Clinical data of group B through the follow up period

     Burden of ventricular ectopics was found to be significantly lowered (p=0.01) through the follow up period with lower incidence and percentage after six months of drug use (Tables 13& 14).

Table (13): Holter study changes through the follow up period in group A

Table (14): Holter study changes through the follow up period in group B

DISCUSSION

     In the PARADIGM-HF trial, sudden cardiac death (SCD) more decreased in the sacubitril/valsartan as compared with ACEIs. A further prospective study recruited patients with HFrEF, treated with sacubitril/valsartan, and compared them with the treatment data on ACEI and/or angiotensin receptor blocker (ARBs) (de Diego and Gonzalez-Torres, 2018).

     However, published data presented six cases of ventricular arrhythmic storm shortly after initiating sacubitril/valsartan that required drug withdrawal Vicent et al., (2019).

     No systematic analysis of the incidence of ventricular tachyarrhythmia in patients treated with sacubitril/valsartan in a sufficient number of patients with long-term follow-up has been conducted yet.

     We conducted a prospective observational study on 60 patients with heart failure with reduced ejection fraction, divided into two groups; 30 patients on Sacubitril/Valsartan combination, and 30 patients on ACEIs or ARBs to evaluate the incidence of ventricular arrhythmia in each group by Holter, with follow up of the Electrocardiogram and Echocardiography within 6 months after drug use. To assess to what extent the patient can benefit from medications to reduce hospitalization and prevent SCD. There was no impact of risk factors among our patients on incidence of arrhythmias in both groups. We missed one of our patients in ACEIs group due to sudden cardiac death in home. But in Sacubitril/Valsartan group we did not lose any of our patients. There was no significant difference regarding hospitalization on top of decomposition between both groups.

     They have found that the functional capacity of Sacubitril/Valsartan groups was improving through the follow up period by documenting their quality of life and according to NYHA classification of HF. Also there was an antiarrhythmic effect of Sacubitril/Valsartan combination therapy, compared to ACEIs characterized by reduced burden of ventricular ectopics through the follow up period by Holter monitoring. The frequency of ectopics after the first three months was 2511 and became 2022 ectopics after 6 months that represent a significant difference with P value 0.012. These results consistent with the study of Martens and Nuyens (2019) that concluded a decrease in the burden of ventricular arrhythmias, as assessed by ICD monitoring.

     In contrast, ACEIs groups did not show reduced frequencies of ventricular ectopics through the follow up period and in contrast the ectopics increased from mean 1221 ectopics in the first three months to become 1878.5 ectopics after 6 months of initiations of medications which represents non-significant difference with P value 0.891 and it was consistent with de Diego and Gonzalez-Torres (2018) who found that Angiotensin-neprilysin inhibition decreased ventricular arrhythmias and appropriate ICD shocks in HFrEF patients under home monitoring compared to angiotensin inhibition Sacubitril/Valsartan group.

     We found non-significant decrease in QTc values which reached the lowest values after 6 months. In contrast ACEIs group was associated with non-significant increase in QTc values through the follow up period to reach the highest values after six months. It was consistent with Valentim Gonçalves (2019) who found that QTc interval were significantly reduced by 5.7% in Sacubitril/Valsartan combination therapy in HFrEF. Runs of NSVT in ACEIs group but not in Sacubitril/Valsartan combination decreased during the follow up; it was against the study of Martens and Nuyens (2019) that concluded that runs of NSVT are higher in ACEIs than Sacubitril/Valsartan combination.

     Ejection fraction was found to be increased in Sacubitril/Valsartan group through the follow up period with high significant difference between its values before drug use and 6 months after treatment, its initial mean EF was 29.77±4.09% and became 31.57±4.49% after 3 months and reached 33.83±4.83% after 6 months of treatment and it represents highly significant difference, it was consistent with Bayard and Decosta (2020) who found that under sacubitril/valsartan, LVEF improvred from 32.6 ± 5 to 36 ± 6% .In contrast in ACEIs group, EF has no significant difference through follow up period.

     LA diameter was found to has significant difference in Sacubitril/Valsartan group after six months of drug use and declined after three months to become (4.75±0.50cm) after six months; In ACEIs group, mean LA diameter was significantly increasing from its initial values after 6 months and it was consistent with Landolfo and Piani (2020) who found also a significant reduction of LA diameter and RVSP was found to have a significant difference in both groups through the 6 months of follow up with highest values before initiation of the drug and lowest values after 6 months and it was also consistent with Martens and Nuyens (2019) who stated that a trend toward reduction in RVSP was noted Martens et al 2019.

CONCLUSION

     Sacubitril/Valsartan combination therapy was superior to ACEIs in reducing ventricular ectopics and decrease in QTc values which reflects the role of this combination to reduce ventricular arrhythmias.

     Ejection fraction in Sacubitril/Valsartan combination group was improving through the follow up period as well as LA dimension, LVID and RVSP which can be explains in reverse remodeling.

     Functional capacity in Sacubitril/Valsartan combinations group was improving through follow up period which means this drug reduces hospitalization.

LIMITATIONS

     The sample was not large enough and was only conducted on 60 patients. Also assessment of functional capacity was subjective without qualitative assessment method to evaluate our patients.

Conflict of interest statement:

     The authors have no conflicts of interest to declare.

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