Sex-Based Response of Heart Rate to Ivabradine in Different Heart Diseases

ABSTRACT IMAGE

INTRODUCTION

Ivabradine selectively inhibits the funny current (I_f) in sinoatrial (SA) nodal tissue, resulting in a decrease in the rate of diastolic depolarization and consequently the heart rate, a mechanism that is distinct from those of other negative chronotropic agents.^[1,2] Ivabradine specifically affects the SA node, having no effect on blood pressure, intracardiac conduction, myocardial contractility, or ventricular repolarization.^[3] As a unique pharmacological agent that is specifically able to reduce the heart rate unaccompanied by side effects common to other similar medications, the expectations of its potential impact within cardiovascular medicine were high. Several small and large studies have evaluated this drug as a therapeutic agent targeting disease conditions in all branches of cardiology (i.e., coronary artery disease [CAD], heart failure [HF] with reduced ejector fraction, chronic stable angina, and electrophysiology).^[4-6] Among all other factors, an increase in heart rate is a significant predictor of cardiovascular mortality and hospitalization in patients with several heart diseases.^[7] Females generally have a slightly higher resting heart rate compared to males, likely due to differences in autonomic regulation, hormonal influences, and cardiac size; since baseline heart rates differ by sex, it is important to evaluate whether ivabradine’s effect on heart rate also differs between males and females.

Hence, in this study, we aim to observe the response of heart rate to ivabradine in different heart diseases and to compare the response in both genders.

Ivabradine acts through selective inhibition of the hyperpolarization-activated cyclic nucleotide-gated channels that mediate the SA nodal funny current (If). This results in a reduced slope of phase 4 diastolic depolarization and a consequent lowering of heart rate. Unlike β-blockers or non-dihydropyridine calcium channel antagonists, ivabradine exerts this negative chronotropic effect without influencing systemic blood pressure, myocardial contractility, atrioventricular conduction, or ventricular repolarization. Its unique mechanism was therefore expected to confer therapeutic advantages in cardiovascular disease (CVD) while avoiding the hemodynamic and electrophysiological limitations associated with other rate-lowering agents. Several placebo-controlled, multicenter clinical studies have shown the effect of ivabradine in the treatment of a variety of CVD, including CAD with left ventricle (LV) systolic dysfunction, chronic HF (CHF), and CAD without clinical HF.^[1,5,6] By adding the heart rate–lowering agent, ivabradine, in patients whose heart rate exceeds 70 beats/min despite beta-blockade (as well as among those who cannot tolerate beta-blockade), the additional heart rate reduction is beneficial. Swedberg et al. evaluated the impact of ivabradine in the presence of a beta-blocker as the background drug in systolic HF patients.^[1] Kaczmarek et al.^[5] found that resting heart rate was significantly reduced among the patients who had both normal and abnormal intrinsic heart rate. In patients with CHF, Mullasari et al.^[6] found that prolonged-release ivabradine given once a day was found to have statistically comparable and desired outcomes of heart rate maintenance.

MATERIALS AND METHODS

This prospective, hospital-based, single-center, observational study was conducted at MKCG Medical College and Hospital, Berhampur, Odisha, over a 2-month period. All patients admitted to the cardiology ward with different heart diseases were screened for eligibility and included if they were above 18 years of age and met the inclusion criteria. Patients with atrial or ventricular pacing, sick sinus syndrome, SA block, second or third-degree atrioventricular block, moderate to severe liver disease, severe renal disease, or anemia were excluded from the study.

Written informed consent was obtained in the local language after explaining the purpose, procedures, and risks involved in the study. The study was approved by the Institutional Ethics Committee (IEC Approval No: EC/NEW/INST/2022/2934, dated August 21, 2024). All patients included in the study were receiving standard guideline-directed therapy, including antiplatelets, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blocker (ARBs), calcium channel blockers, beta-blockers, angiotensin receptor-neprilysin inhibitor (ARNI), statins, mineralocorticoid receptor antagonist (MRAs), and diuretics as indicated.

Baseline anthropometric parameters, including height, weight, and body mass index (BMI), were recorded. Blood pressure was measured using a mercury sphygmomanometer after a 15-min rest in the sitting position. Baseline heart rate was recorded. After initiating ivabradine therapy in guideline-approved doses, patients were re-evaluated after 2 weeks using the same parameters to assess the heart rate response.

The collected data were entered into Microsoft Excel and analyzed using the Statistical Package for Social Sciences version 29.0. Appropriate statistical tests were applied, and P < 0.05 was considered statistically significant.

RESULTS

In the present study, most of the patients were male (59.2%), with a mean age of 61.43 years [Figure 1]. The mean height, weight, and BMI of the patients were 161.47 cms, 64.06 kgs, and 24.68, respectively. Ischemic cardiomyopathy (ICMP) (32.7%), followed by ST elevated myocardial infarction (STEMI) (28.6%), and dialated cardiomyopathy (DCMP) were the most common heart diseases reported among the included patients [Figure 2]. The mean heart rate at baseline and after 2 weeks was 92.63 and 69.37/min, respectively. Among the patients, 71.4% had their dose of ivabradine changed from baseline by the time of 2 weeks to achieve the heart rate, while 28.6% of the patients had their dose retained. Overall, 73.5% of the patients had achieved the heart rate after 2 weeks of the initiation of the ivabradine [Table 1 and Figure 3].

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Figure 1:

Distribution of both gender in the study.

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Figure 2:

Distribution of different heart diseases in the study. (STEMI: ST elevated myocardial infarction, NSTEMI: Non ST elevated myocardial infarction, ICMP: Ischemic cardiomyopathy, DCMP: Dilated cardiomyopathy.)

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Figure 3:

Distribution of heart rate achieved in both the genders.

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While 86.2% of the males achieved heart rate following the ivabradine administration, 55% of the women achieved the heart rate, which was statistically significant [Table 2].

In 2.5 dose, only one case (female) was present who achieved the heart rate. While all the males achieved heart rate following the ivabradine administration of dose 5, 71.4% of the women in the same dose achieved the heart rate, which was statistically significant. No significant association between sex and heart rate achieved was noted in the ivabradine dose of 7.5 [Table 3 and Figure 4-6].

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Figure 4:

Sex versus heart rate achieved.

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Figure 5:

Sex versus heart rate achieved in dose of 5.

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Figure 6:

Sex versus heart rate achieved in dose of 7.5.

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No significant association between sex and heart rate achieved was noted among the patients with different heart diseases [Table 4 and Figures 7, 8, 9a, and b].

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Figure 7:

Sex versus heart rate achieved in STEMI. (STEMI: ST elevated myocardial infarction.)

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Figure 8:

Sex versus heart rate achieved in NSTEMI. (NSTEMI: Non ST elevated myocardial infarction.)

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Figure 9:

(a) Sex versus heart rate achieved in ICMP. (b) Sex versus heart rate achieved in DCMP. (ICMP: Ischemic cardiomyopathy, DCMP: Dilated cardiomyopathy.)

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DISCUSSION

The heart rate of 70 beats/min in patients receiving beta-blockers, as well as in those who are not, due to medication intolerance, was significantly associated with an increased risk of HF exacerbation or mortality attributable to HF.^[1] The present study was undertaken among 49 patients, among which ICMP (32.7%), followed by STEMI (28.6%), and DCMP were the most common heart diseases reported among the included patients. They were assessed over a 2-week period for the impact of the ivabradine on the heart rate.

While the mean age of the patients was 61.43 years in the present study, Kaczmarek et al.^[5] in their study evaluating the impact of ivabradine therapy among the patients who had inappropriate sinus tachycardia from Poland included relatively younger patients in their study (33.1– 37.4 years). Mullasari et al.^[6] from Chennai, India, included patients with a mean age of 53–55 years, closer to the age of the patients in our study. Swedberg et al. evaluated the impact of ivabradine in the presence of a beta-blocker as the background drug in systolic HF patients.^[1]

In the present study, the majority of the patients were male (59.2%). This is in line with most of the previous studies, which also included males as the majority.^[2,3] Most of the previous studies undertook the evaluation of the impact of ivabradine through the lens of gender, which has been the primary objective of the present study. Ali et al. from Pakistan also undertook a subgroup analysis based on gender to compare the association between gender and efficacy of ivabradine (which was compared with traditional therapy).^[4]

The decrease in heart rate with ivabradine has demonstrated improvement in clinical parameters for individuals with HF, surpassing the benefits seen with beta-blockers.^[1,5,6] (Swedberg 2012, Fox, Bohm). Ivabradine inhibits the operation of the pacemaker in a selective and particular manner. In the event, If ionic current, which exerts its influence on the SA node, leads to a decrease in heart rate.^[3]

In the present study, a significantly higher proportion of males had achieved heart rate than females, following the therapy with ivabradine. However, when analyzed based on the dose of ivabradine administered, this significantly higher success rate in males was present was present only for the dose of 5, while no such difference was noted in the dose of 7.5. Ali et al. who reported a significantly better efficacy in the ivabradine group of patients than the traditional therapy group, both in males and females.^[4] The variation in the findings might be due to the difference in the biological traits (different study population), disease condition (only CHF patients included in Ali et al.), and study design (compared with another group of intervention). Another difference might be due to the varied follow-up time. While it was 2 weeks in our study, Ali et al. reported findings after 2 months. Other studies in the past evaluating the efficacy of ivabradine among the various heart disease conditions echoed our findings in terms of heart rate reduction.^[4] In the present study, a significantly higher proportion of males achieved target heart rate than females following ivabradine therapy, with the most notable difference at the 5 mg dose. This sex-specific variation is consistent with previous mechanistic and clinical analyses from Koruth et al.^[7], Boating et al.^[8], and Balmborth et al.^[9], supporting the biologic plausibility of differential heart rate response. Additionally, the ESC 2021 Guidelines support ivabradine use in chronic HF where HR control is insufficient despite β-blockers.^[10] Evidence from Pal et al. 2015 demonstrates beneficial effects of ivabradine on LV relaxation in HFpEF.^[11] Furthermore, a 2022 meta-analysis by Maagaard et al. supports the incremental benefit of ivabradine added to standard HF therapy.^[12]

Kaczmarek et al.^[5] found that resting heart rate was significantly reduced among the patients who had both normal and abnormal intrinsic heart rate. Studies have compared also compared the efficacy of the different formulations of ivabradine. In patients with CHF, Mullasari et al.^[6] found that prolonged-release ivabradine given once a day was found to have statistically comparable and desired outcomes of heart rate maintenance.^[3] Although the present study did not compare the variants of formulations, there is a scope for further research in this domain to compare between the formulations of ivabradine. Ivabradine demonstrated a reduction in heart rate, which was associated with clinical benefit in patients already receiving beta-blockers, and was also associated with improved outcomes such as reductions in hospitalizations for heart failure.^[1]

There was no significant association between the sex and the heart rate achieved within the type of heart disease (STEMI, NSTEMI, ICMP, and DCMP) among the patients included in the present study. While most of the previous studies were restricted to certain heart disease, the present study included patients with heart diseases, thus improving the applicability of the findings to those conditions.

CONCLUSION

Overall, ivabradine had a significant, desirable reduction in the heart rate among the patients with heart diseases. Male gender might have a significantly better association with desirable reduction in the heart rate in the current settings. The mechanism behind the role of gender on the efficacy of ivabradine needs to be explored further in future studies. Further, multicentric, comparative studies with long-term follow-up needs to be undertaken to confirm and improve the validity of our findings.