The FDA approved Ivabradine to reduce the rate of hospitalization and cardiovascular-related death in patients with HFrEF, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either is on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use [8].

In our study, a total of 64 patients were enrolled and followed up for 6 months for the occurrence of primary objective MACE and for other secondary outcomes. The median (IQR) age of patients in the study groups was 57 (50–62) and 58.50 (55–67) in the IVA + BB group and BB group, respectively, depicting that the patients in both groups were similar for age. The mean age of patients included in our study was lower than compared to other studies, such as SHIFT & INTENSIFY trial, while the gender distribution was comparable.

In the SHIFT trial, the mean age of patients in the ivabradine group was 60.7 ± 11.2 and 60.1 ± 11.5 in the placebo group, and in the INTENSIFY study, the mean age was 67 ± 11.7, and this further supports our result that a similar age group patients were included in our study. The gender-wise distribution showed that most patients were male, 80% in the IVA + BB group and 91.2% in the BB group; this was similar to gender observed in other major trials like the SHIFT and ETHIC-AHF study. In the SHIFT trial, 76% of patients were male, and in the ETHIC-AHF study, 71.9% were male [14, 15].

The analysis of the primary composite endpoint MACE in our study showed no significant difference between the study groups. Even though the hazard ratio for MACE was 1.13, indicating that there were increased events in the IVA + BB group, and the heart rate is one of the variables directly correlated with the number of adverse cardiac events [16]. In our study, HR was one of the inclusion criteria; patients with HR (35) ≥ 80bpm were included in the IVA + BB group, and patients with HR < 80 bpm were included in the BB group and were followed for six months for the occurrence of primary and secondary events. Since it is an observational study, and due to ethical reasons, we could not make the groups comparable concerning HR. Hence, the baseline mean heart rate in the IVA + BB group was 93.73 ± 10.33, and 71.71 ± 5.80 in the BB group. There was a 22bpm difference in HR between the study groups at baseline. In the SHIFT study, Bohm et al., in 2010, studied the association between HR and adverse cardiovascular outcomes, in which they found that for every beat increase in HR, there was a 3% increase in the risk of the primary composite endpoint (cardiovascular death and hospitalization for HF) [16]. Upon extrapolating, the patients in the IVA + BB group had a 66% increased risk of occurrence of events at baseline; despite that, the number of MACE events in the IVA + BB group was similar (5-IVA + BB; 5-BB), indicating that ivabradine in addition to standard care decreased the occurrence of adverse cardiac outcomes. This can be further supported by another study, a meta-analysis done by Zhang D. et al. in 2016, to observe the effect of higher resting heart rate on all-cause and cardiovascular mortality in the general population [17]. The authors have quoted that for every 10-beat increment in resting heart rate, the risk of all-cause and cardiovascular mortality increased by 9% and 8%, respectively. Also, a much more significant increase in risk of cardiovascular mortality was observed in patients with HR > 90 bpm [17].

Regarding the dose of ivabradine in our study, the initial starting dose was 5mg, and most patients in the combination group were maintained in this dose. Only in one patient was the dose increased to 7.5mg due to inadequate control of HR. The average reduction of HR at 6 months in the ivabradine + beta-blocker group was 13.84 bpm, which was a significant difference when compared to the baseline HR (p = 0.001). The results observed in our study were parallel to those observed in the SHIFT and INTENSIFY studies. The study drug ivabradine was well tolerated in our study population; only two patients have stopped ivabradine due to bradycardia but were asymptomatic and found during regular visits to the outpatient department.

In the SHIFT study, treatment with ivabradine caused an average reduction of 15 bpm from a baseline value of 80 bpm. In the INTENSIFY study, there was a 15.4 bpm reduction in HR from a baseline value of 79.9 bpm [18]. Further, therapy with ivabradine should be discontinued if the heart rate is < 50bpm at a dose of 2.5mg twice daily. In SHIFT trial, 1% of patients had a specific adverse effect called phosphenes that are transient brightness in the visual field triggered by exposure to bright light. In our study, this adverse effect was not reported in patients prescribed ivabradine. Since our sample size was small, further studies with larger sample sizes may light up the incidence of this adverse effect in the Indian population.

In our study, the maximum tolerated dose for beta-blocker was 100mg daily, and most of the patients in both groups attained less than or equal to 50% of the target dose. In SHIFT study also, only 26% of patients reached the target dose in both the ivabradine and placebo groups [4].

In our study, we observed that the LVEF% is not directly related to the symptomatology; few patients with LVEF < 15% were in the NYHA class II category, and in few patients, even with LVEF of 30%, the NYHA grade was IV, although LVEF is useful, in classifying patients as HFrEF or HFpEF and for the management of HF. We also categorized patients according to LVEF as > 35%, 25–35%, and < 25%. Most patients had LVEF 25–35%, 66.7% in the IVA + BB group, and 76.5% in the BB group, which was insignificant. During follow-up, 10.3% of patients in the IVA + BB group and 6.1% in the BB group had improvement in LVEF (> 35%), but this improvement was insignificant. One patient in the IVA + BB group and one patient in the BB group had undergone coronary artery bypass graft surgery and angioplasty and had improvement in LVEF (> 35%). In the INTENSIFY study, the proportion of patients with LVEF < 35% decreased from 26.6% at baseline to 17.4% at 4 months, but the authors did not mention whether this result was significant. However, the authors claimed an improvement in LVEF; this could be attributed to the higher number of patients included in their study (n = 1941) compared to our study (n = 64). (16).

The quality of life in our study was assessed using Minnesota Living with Heart Failure Questionnaire. This was done in two time points at baseline and at three months in both the study groups; the score correlated with poorer response. At baseline, the total scores, physical domain score (PDS) (Item No-2,3,4,5,6,7,12,13), emotional domain score (EDS) (Item No-17,18, 19, 20, 21), and social domain score (SDS) (Item No-8, 9, 10, 14, 15, 16) between the groups were similar and did not show any significant difference. During follow-up at 3 months, the total scores, PDS, EDS and EDS showed no significant improvement in the IVA + BB or BB group. However, the total score was somewhat decreased, from 36 to 28 in IVA + BB, but not in the BB group (Tables 3 and 4).

The most common reason told by the patients for nonadherence is cost of drug in both the groups. Regarding the COVID-19 vaccination, we have found that increased proportion of patients, that is 62.1% in ivabradine + beta-blocker group and 51.5% in beta-blocker group, were not vaccinated for COVID-19. The common reasons quoted by the patients were hesitancy due to patient’s co-morbid condition and fear of adverse drug reactions due to COVID-19 vaccine. Compared to ivabradine + beta-blocker group, the vaccination rate in beta-blocker group was higher, but it was not significant.