Optimizing Heart Rate with Ivabradine in Heart Failure with Reduced Ejection Fraction: Insights from a Post-Hoc Analysis of the SHIFT Trial

This article refers to ‘Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction’ by M. Böhm et al., published in this issue on pages 1429–1435. Heart failure with reduced ejection fraction (HFrEF) is a significant public health concern worldwide, contributing to a heightened burden of disease, mortality, and increasing healthcare expenses.1 Current societal guidelines recognize the importance of rapid initiating and expedited titration of guideline-directed medical therapy (GDMT) among patients with HFrEF.2, 3 Most of current GDMT medications such as renin–angiotensin system blockers, mineralocorticoid receptor antagonists, and sodium–glucose cotransporter 2 inhibitors, have early onset therapeutic effects; however, they lack the therapeutic impact on reducing heart rate (HR), a known modifiable risk factor in HFrEF. The sympathetic and parasympathetic nervous systems work in precise balance to regulate HR. In the state of HFrEF, the impaired myocardial function causes an excessive stimulation of the sympathetic tone, which attempts to restore cardiovascular homeostasis.4, 5 Pharmacologically, to achieve a reduction in HR, there are two main mechanisms: a direct and an indirect modulation in the cardiovascular system. The direct modulation occurs when the medication directly blocks sinoatrial node channels resulting in achieving lower HR. Ivabradine is an example of this mechanism which blocks sinoatrial node If channels.6 The indirect modulation occurs when HR is manipulated by changing the tone of the autonomic nervous system such as the case of beta-blockers. Digoxin has a mixed effect on HR, as it increases vagal tone and partially modulates the sinoatrial node.7 In the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960), there were multiple signals indicating the importance of achieving a better HR control among patients with HFrEF (defined in SHIFT trial as left ventricular ejection fraction ≤35%). SHIFT was the first randomized, double-blind, placebo-controlled trial to examine the isolated effect of HR reduction among HFrEF patients. Before being enrolled in the SHIFT trial, patients were required to have received the maximum tolerable dose of beta-blocker therapy (with 82–93% of them having been on beta-blockers), had baseline sinus rhythm with HR ≥70 bpm. The titration period for ivabradine in the SHIFT trial was 28 days to achieve a resting HR ≤70 bpm while ensuring tolerability. At the end of the titration period, almost two thirds of placebo group (n = 2074/3264; 63.5%) did not achieve resting HR of ≤70 bpm, while only one-quarter of ivabradine group (n = 849/3241, 26.2%) failed to achieve the HR target of ≤70 bpm. Among patients who were able to achieved a resting HR of <60 bpm, they had a lower event rate of 17.4% (95% confidence interval [CI] 15.3–19.6) compared to patients who had HR of ≥75 bpm with event rate of 32.4% (95% CI 28.6–36.6) (p-values were not significant). The SHIFT trial concluded that every 5 bpm increase in HR was associated with roughly a 16% increase in the risk of primary composite endpoint events (i.e. cardiovascular death or hospital admission for worsening heart failure) (Figure 1).8 In this issue of the Journal, Böhm and colleagues performed a post-hoc analysis on the SHIFT trial and examined the question on duration of HR reduction among HFrEF and its significance on adverse cardiovascular events.9 The authors classified the SHIFT cohort into two main groups: overall population with a baseline resting HR ≥70 bpm and the population with a baseline resting HR ≥75 bpm. Among patients with baseline HR ≥70 bpm, ivabradine significantly reduced the primary outcome – defined as cardiovascular death and heart failure hospitalization (HFH) – as well as HFH at 102 days (hazards ratio [HR] 0.82, 95% CI 0.67–1.00; and HR 0.78, 95% CI 0.62–0.98, respectively). Among patients with baseline HR ≥75 bpm, a reduction of the primary outcome occurred only after 67 days (HR 0.74, 95% CI 0.56–0.98), HFH occurred at 78 days (HR 0.72, 95% CI 0.53–0.99) as well as cardiovascular death after 169 days (HR 0.72, 95% CI 0.52–1.00).9 Although these findings may contribute to better outcomes among patients with HFrEF, this analysis carries several limitations. Firstly, in the SHIFT trial, the majority of randomized patients were of White race (averaging 88.6% across multiple HR groups at baseline) and the majority of patients were men (>76%), which limits the generalizability of these findings to overall HFrEF patients. Multiple investigation among patients with heart failure revealed differences in the baseline HR between difference races (i.e. White race vs. Black race).10, 11 Secondly, this post-hoc analysis may have less reliable conclusions than pre-planned analyses due to potential biases from selective data analysis, which can lead to overestimation of treatment effects, as well as a lack of statistical power and control for confounding factors.12 However, the presence of a considerable number of patients in each subgroup ensures sufficient statistical power to accurately detect significant differences. Despite these limitations, the reduction of HR in patients with HFrEF by ivabradine is a desirable outcome. Prior trials have demonstrated the positive impact of HR reduction therapy on adverse cardiovascular outcomes. BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) trial examined the clinical benefit of ivabradine among HFrEF and coronary artery disease. Enrolling more than 10 000 patients, the trial showed that ivabradine did not significantly decrease the primary endpoint (cardiovascular death, acute myocardial infarction, and heart failure), but it did decrease the secondary endpoints (i.e. admission for myocardial infarction and coronary revascularization). This effect was more pronounced in patients with a symptom of limiting angina and baseline HR ≥70 bpm (HR 0. 27, 95% CI 0.11–0.66; p = 0.002).13 This finding in the BEAUTIFUL trial highlights the potential benefits of HR reduction in improving clinical outcomes beyond heart failure, specifically in reducing the need for coronary revascularization. Consideration for ivabradine for lowering HR should be considered after attempting to maximize the dose of beta-blockers among HFrEF patients. The impact of beta-blockers on HFrEF extends beyond controlling HR; thus, their survival benefit cannot be attributed solely to lowering HR. Two meta-analyses of over 35 randomized clinical trials, including more than 23 000 patients with HFrEF on beta-blockers, have shown a strong signal toward reducing mortality and hospitalization rates with higher doses of beta-blockers, which is achieved by lowering HR.14, 15 Non-dihydropyridine calcium channel blockers, which are used to reduce HR, are typically avoided in heart failure and contraindicated in HFrEF due to their pronounced negative inotropic effect.7 The assessment of HR is an integral part of managing patients with HFrEF, and increasing evidence supports the plausibility of elevated resting HR as a pathophysiological mediator of adverse cardiovascular outcomes. Although ivabradine has demonstrated a reduction in the risk of cardiovascular death and HFH, particularly in patients with higher baseline HR, this reduction was more pronounced in patients with baseline HR ≥75 bpm (i.e. 67 days) compared to patients with baseline HR ≥70 bpm (reduction occurred at 102 days). It is imperative for clinicians to reserve ivabradine for patients who are intolerant or contraindicated to other recommended therapies, or those with persistently high HR despite treatment with other agents. Future studies are necessary to validate the results of the SHIFT trial and investigate the onset of therapeutic effect of ivabradine in patients with HFrEF. Conflict of interest: none declared.