Outcomes of left bundle branch area pacing compared to His bundle pacing as a primary pacing strategy: Systematic review and meta-analysis.

BACKGROUND: Novel pacing technologies, such as His bundle pacing (HBP) and left bundle branch area pacing (LBBaP), have emerged to maintain physiological ventricular activation. We investigated the outcomes of LBBP with HBP for patients requiring a de novo permanent pacing. METHODS AND RESULTS: Systematic review of randomized clinical trials and observational studies comparing LBBaP with HBP until March 01, 2023 was performed. Random and fixed effects meta-analyses of the effect of pacing technology on outcomes were performed. Study outcomes included pacing metrics, QRS duration, lead revision, procedure parameters, all-cause mortality and heart failure hospitalization (HFH). Overall, 10 studies with 1596 patients were included. Implant success rate was higher in LBBaP compared with HBP (RR 1.24, 95% CI: 1.08 to 1.42, p = .002). LBBaP was associated with lower capture threshold at implantation (mean difference (MD) -0.62 V, 95% CI: -0.74 to -0.51 V, p < .0001) and at follow-up (MD -0.74 V, 95% CI: -0.96 to -0.53, p < .0001), shorter procedure duration (MD -14.66 min, 95% CI: -23.54 to -5.78, p = .001) and shorter fluoroscopy time (MD -4.2 min, 95% CI: -8.4 to -0.0, p = .05). Compared with HBP, LBBaP was associated with a decreased risk of all-cause mortality (RR: 0.50, 95% CI: 0.33 to 0.77, p = .002) and HFH (RR: 0.57, 95% CI: 0.33 to 1.00, p = .05). No statistical differences were found in lead revisions and QRS duration before and after pacing. CONCLUSION: This meta-analysis found that LBBaP was superior to HBP regarding pacing metrics and implant success rate as an initial pacing strategy, although absence of head-to-head randomized comparison warrants caution in interpretation of the results.

European Society of Cardiology Quality Indicators for the care and outcomes of cardiac pacing: developed by the Working Group for Cardiac Pacing Quality Indicators in collaboration with the European Heart Rhythm Association of the European Society of Cardiology.

AIMS: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults undergoing cardiac pacing. METHODS AND RESULTS: Under the auspice of the Clinical Practice Guideline Quality Indicator Committee of the European Society of Cardiology (ESC), the Working Group for cardiac pacing QIs was formed. The Group comprised Task Force members of the 2021 ESC Clinical Practice Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy, members of the European Heart Rhythm Association, international cardiac device experts, and patient representatives. We followed the ESC methodology for QI development, which involved (i) the identification of the key domains of care by constructing a conceptual framework of the management of patients receiving cardiac pacing, (ii) the development of candidate QIs by conducting a systematic review of the literature, (iii) the selection of the final set of QIs using a modified-Delphi method, and (iv) the evaluation of the feasibility of the developed QIs. Four domains of care were identified: (i) structural framework, (ii) patient assessment, (iii) pacing strategy, and (iv) clinical outcomes. In total, seven main and four secondary QIs were selected across these domains and were embedded within the 2021 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization therapy. CONCLUSION: By way of a standardized process, 11 QIs for cardiac pacing were developed. These indicators may be used to quantify adherence to guideline-recommended clinical practice and have the potential to improve the care and outcomes of patients receiving cardiac pacemakers.

Management strategies in heart failure with preserved ejection fraction.

The diagnosis and therapy of heart failure with preserved ejection fraction (HFpEF) remain challenging. Currently, there are ongoing discussions on whether the diagnosis of HFpEF should be based solely on left ventricular ejection fraction, which may not account for the heterogeneity of HFpEF syndrome. This aspect has been addressed by the recently proposed HFA-PEFF and the H2FPEF algorithms, which take numerous diagnostic modalities into account to establish the diagnosis of HFpEF. Moreover, this review focuses on the adequate treatment of comorbidities and risk factors in HFpEF that should be an essential part of any HFpEF therapy. Furthermore, the management of fluid level in HFpEF patients is pointed out, as it plays an important role in symptom control. In addition, the value of LCZ696 therapy in HFpEF is discussed. Although LCZ696 had neutral effects in the large PARAGON-HF trial, it had previously been granted an extended indication by the Food and Drug Administration. Since the publication of the EMPEROR-Preserved trial, empagliflozin now represents the first drug to significantly improve the prognosis of HFpEF patients. Therefore, the role of SGLT2 inhibitors in HFpEF management is highlighted. Overall, this review aims to enhance the knowledge on the diagnostic processes and best treatments available for HFpEF patients.

Efficacy and Safety of Cryoballoon Ablation in Patients With Heart Failure and Reduced Left Ventricular Ejection Fraction　- A Multicenter Study.

BACKGROUND: Second-generation cryoballoon (CB2)-based pulmonary vein isolation (PVI) has demonstrated encouraging results in the treatment of atrial fibrillation (AF). This study sought to assess data on the safety, efficacy and clinical success of CB2-based PVI in patients with heart failure (HF) and reduced ejection fraction (HFrEF).Methods and Results:CB2-based PVI was performed in 551 consecutive patients in 3 highly experienced EP centers. Patients with HF and LVEF ≤40% were included (HFrEF group, n=50/551, 9.1%). Data were compared with propensity score-matched patients without HF and preserved left ventricular EF (LVEF) (n=50, control group). The median LVEF was HFrEF: 37% (35, 40) and control: 55% (55, 55), P<0.0001. Major periprocedural complications were registered in 4/50 (8%, HFrEF group) and 3/50 (6%, control group), P=0.695. The 12-month freedom from AF recurrence was 73.1% (95% confidence interval (CI): 61-88, HFrEF group) and 72.6% (95% CI: 61-87, control group), P=0.25. NYHA class decreased from 2.4±0.8 (baseline) to 1.7±0.8 at 12-month follow-up (P<0.0001). LVEF improved from a median of 37% (35, 40) prior to ablation to a median of 55% (40, 55), P<0.0001. CONCLUSIONS: CB2-based PVI in patients with HFrEF appeared to be safe, was associated with comparable periprocedural complications and showed promising clinical success rates equal to those for patients with preserved LVEF. NYHA class and LVEF significantly improved at 12-month follow-up.

Incidence and predictors of pacemaker induced cardiomyopathy: A single-center experience.

BACKGROUND: Pacemaker induced Cardiomyopathy (PICM) is an easily overlooked cause of heart failure with reduced ejection fraction. Data regarding this complication are sparse. Therefore, the aim of this study was to identify the incidence and predictors of PICM. METHODS: Between 2011 and 2017, 857 consecutive patients undergoing pacemaker (PM) implantation, were reviewed, and according to our inclusion criteria 173 individuals were enrolled in this retrospective single center study. All patients included had normal left ventricular ejection fraction (LVEF) before implantation, underwent single-chamber ventricular or dual-chamber PM implantation, had RV pacing burden ≥20%, and repeated echocardiogram was available ≥1 year after implantation. PICM was defined as deterioration LVEF ≥10%, resulting in LVEF <50%, which cannot be explained by other causes. RESULTS: During a mean follow-up of 39.9 ±â€¯21.0 months, PICM occurred in 26 patients (16%). RV pacing percentage did not differ significantly between the both groups (76.5 vs 76.2%, p = 0.65). The PICM group patients were likely to be men (p = 0.002) and had a lower rate of arterial hypertension (p = 0.01). Multivariate analysis revealed male sex (HR 6.45, 0.95 CI 1.90-21.86, p = 0.003) and wider paced QRS complex (HR 1.04, 95% CI 1.02-1.07, p < 0.001) as predictors of PICM. CONCLUSIONS: In patients with frequent RV pacing, the prevalence of PICM is not uncommon. Male sex and wider paced QRS complex are independent predictors of PICM and these patients may require closer follow-up.

Ablation Index for Catheter Ablation of Atrial Fibrillation　- Clinical Applicability and Comparison With Force-Time Integral.

BACKGROUND: Key determinants for lesion formation in catheter ablation are contact force, radiofrequency (RF) power and time. The aim of this study was to evaluate the clinical applicability of ablation index (AI), a novel non-linear formula based on these components, and to compare AI with the conventional linear force-time interval (FTI) in pulmonary vein isolation (PVI). Methods and Results: Target AI ranges were defined for anatomical segments of the ipsilateral pulmonary veins. The operator was blinded to AI during PVI for the initial 11 patients (group A), and was unblinded for the remaining 23 patients (group B). We assessed (1) the clinical value of AI to avoid excessively high and low values with an operator blinded vs. non-blinded to AI; and (2) the relation of AI and FTI in predefined ranges. In group A, 235/564 lesions (41.7%) were in the predefined target range as compared with 1,171/1,412 lesions (82.9%) in group B (P<0.001). A given AI may correspond to a wide range of FTI, as reflected by a quartile coefficient of dispersion for AI of 0.11 vs. a quartile coefficient of dispersion for FTI of 0.36. CONCLUSIONS: Incorporating RF current power, the non-linear AI provides more comprehensive information during PVI compared with FTI. Given that the FTI for a given AI varies widely, the value of FTI in clinical practice is questionable.

Bioresorbable Vascular Scaffolds in a Real-World Patient Population-Results From a Mid-Term Angiographic Follow-Up.

AIM: We aimed to investigate the safety and efficacy of bioresorbable vascular scaffolds (BVS) in daily use in a real-world patient population. METHODS AND RESULTS: Between March 2013 and September 2014, 224 patients (233 lesions) were treated with BVS at a tertiary care center. Patients underwent follow-up coronary angiography 3-6 months after implantation. Clinical presentations were stable angina in 101 patients (45.1%), unstable angina in 47 (21.0%), NSTEMI in 38 (17.0%), and STEMI in 38 (17.0%) patients. Twenty-two patients (27 lesions) had chronic total occlusion (CTO). Procedural success was achieved in all patients. Two patients died in the follow-up period due to BVS thrombosis (0.9%). In-hospital death occurred in further 3 patients (1.3%) due to other causes not related to the BVS implantation. Total BVS thrombosis was 3.1% (7 patients) and there was only 1 case of relevant restenosis on angiographic follow-up. The overall incidence of major adverse cardiac events was 11 (4.9%). CONCLUSIONS: Mid-term follow-up after implantation of BVS suggests a satisfactory safety profile and low restenosis rate in routine daily practice involving a large range of complex lesions.

[Therapy of heart failure with reduced pump function]. / Therapie der Herzinsuffizienz mit reduzierter Pumpfunktion.

HFrEF causes significant morbidity and mortality and represents a major public health burden. Recently, there have been significant scientific advances in the treatment of HFrEF, with ARNI, BB, MRA, and SGLT-2i forming the GDMT for HFrEF. Basic quadruple therapy has been shown to significantly reduce of HF hospitalizations, all-cause mortality, and cardiovascular mortality. In addition, new initiation and titration procedures have recently been introduced that may progressively improve the management and prognosis of HFrEF. Further efforts are also needed to improve the use of GDMT, which is currently underutilized.

Heart failure with preserved ejection fraction epidemiology, pathophysiology, diagnosis and treatment strategies.

The prevalence of HF with preserved ejection raction (HFpEF, with EF ≥50%) is increasing across all populations with high rates of hospitalization and mortality, reaching up to 80% and 50%, respectively, within a 5-year timeframe. Comorbidity-driven systemic inflammation is thought to cause coronary microvascular dysfunction and increased epicardial adipose tissue, leading to downstream friborsis and molecular changes in the cardiomyocyte, leading to increased stiffness and diastolic dynsfunction. HFpEF poses unique challenges in terms of diagnosis due to its complex and diverse nature. The diagnosis of HFpEF relies on a combination of clinical assessment, imaging studies, and biomarkers. An additional important step in diagnosing HFpEF involves excluding certain cardiac diagnoses that may be specific underlying causes of HFpEF or may be masquerading as HFpEF and require specific alternative treatment approaches. In addition to administering sodium-glucose cotransporter 2 inhibitors to all patients, the most effective approach to enhance clinical outcomes may involve tailored therapy based on each patient's unique clinical profile. Exercise should be recommended for all patients to improve the quality of life. Glucagon-like peptide-1 1 agonists are a promising treatment option in obese HFpEF patients. Novel approaches targeting inflammation are also in early phase trials.

Neuromodulation interventions in the management of heart failure.

Despite remarkable improvements in the management of heart failure (HF), HF remains one of the most rapidly growing cardiovascular condition resulting in a substantial burden on healthcare systems worldwide. In clinical practice, however, a relevant proportion of patients are treated with suboptimal combinations and doses lower than those recommended in the current guidelines. Against this background, it remains important to identify new targets and investigate additional therapeutic options to alleviate symptoms and potentially improve prognosis in HF. Therefore, non-pharmacological interventions targeting autonomic imbalance in HF have been evaluated. This paper aims to review the physiology, available clinical data, and potential therapeutic role of device-based neuromodulation in HF.

Cardio-ocular syndrome: Retinal microvascular changes in acutely decompensated heart failure.

AIMS: To investigate the changes in retinal microvasculature by contemporary imaging techniques during episodes of acute decompensated heart failure (ADHF) and following recompensation compared to age-matched controls without known cardiac or retinal disease. METHODS AND RESULTS: Adult patients hospitalized with a primary diagnosis of ADHF, regardless of left ventricular ejection fraction (LVEF) and treated with a minimum dose of 40 mg of intravenous furosemide or equivalent were included. Transthoracic echocardiography was conducted in all patients. Eye examinations were performed out within the initial 24 h after admission and after recompensation before discharge. All eyes underwent a general examination, including a best corrected visual acuity test, dilated fundoscopy, spectral-domain optical coherence tomography (OCT) as well as OCT angiography (OCT-A). In addition, 40 participants without documented cardiac or retinal diseases served as controls. Forty patients with ADHF (mean age 78.9 ± 8.8 years; 32% female) with a mean LVEF of 43 ± 12.8% were included. All patients were treated with intravenous diuretics for a median of 4.3 ± 2.8 days. There was a significant reduction in N-terminal pro-B-type natriuretic peptide from baseline up to discharge (10 396 [interquartile range 6410] vs. 6380 [interquartile range 3933] pg/ml, p ≤ 0.001) and inferior vena cava diameters (2.13 ± 0.4 vs. 1.63 ± 0.3 cm, p = 0.003). Compared to the control group, patients with ADHF showed on admission impaired visual acuity (0.15 ± 0.1 vs. 0.35 ± 0.1 logMAR, p < 0.001), reduced macular vessel density (18.0 ± 1.9 vs. 14.3 ± 3.6 mm/mm2, p < 0.001) and perfusion density (42.6 ± 3.2 vs. 35.2 ± 9.7%, p < 0.001). After recompensation, the mean overall vessel density and mean overall perfusion density were markedly increased at discharge (14.3 ± 3.6 vs. 19.7 ± 2.6 mm/mm2, p = 0.001, and 35.2 ± 9.7 vs. 39.2 ± 6.5%, p = 0.005, respectively). The mean diameter of the superior temporal retinal vein at admission was significantly larger compared to the control group (136 ± 19 vs. 124 ± 22 µm, p = 0.008) and decreased significantly to 122 ± 15 µm at discharge (p < 0.001). CONCLUSION: This analysis revealed a remarkable reversible change in retinal microvasculature after ADHF. This could provide a valuable evidence for use of OCT-A in the assessment of overall microperfusion and haemodynamic status in patients with acute heart failure.

Effects of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction: An analysis of DAPA-HF and DELIVER.

AIMS: The primary aim was to evaluate the effect of dapagliflozin according to QRS duration across the spectrum of left ventricular ejection fraction (LVEF), given that prolongation of QRS duration is associated with less favourable ventricular remodelling with pharmacological therapy and worse outcomes. METHODS AND RESULTS: A pooled analysis of the DAPA-HF and DELIVER trials, excluding patients with a paced rhythm and cardiac resynchronization therapy. Overall, 4008 patients had heart failure (HF) with reduced ejection fraction (HFrEF), and 5816 had HF with mildly reduced/preserved ejection fraction (HFmrEF/HFpEF). QRS duration was <120 ms in 7039 patients (71.7%), 120-149 ms in 1725 (17.6%), and ≥150 ms in 1060 patients (10.8%). The median follow-up time was 23 months. The rate of the primary composite outcome of cardiovascular death or worsening HF was 9.2 (95% confidence interval [CI] 8.7-9.7), 14.3 (13.0-15.7), and 15.9 (14.1-17.9) per 100 patient-years in the <120, 120-149, and ≥150 ms groups, respectively. This gradient in event rates was observed both in HFrEF and HFmrEF/HFpEF. Dapagliflozin, compared with placebo, reduced the risk of the primary outcome consistently across the QRS duration subgroups (hazard ratio [95% CI] 0.75 [0.67-0.85], 0.79 [0.65-0.96], and 0.89 [0.70-1.13] in the <120, 120-149, and ≥150 ms groups, respectively; p for interaction = 0.28). The effect of dapagliflozin on the primary outcome was consistent across the QRS duration regardless of HF phenotype that is, HFrEF or HFmrEF/HFpEF. CONCLUSIONS: Prolongation of QRS duration is associated with worse outcomes irrespective of HF phenotype. Dapagliflozin reduced the risk of the primary outcome, regardless of QRS duration, in DAPA-HF and DELIVER.

European Society of Cardiology quality indicators update for the care and outcomes of adults with heart failure. The Heart Failure Association of the ESC.

AIMS: To update the European Society of Cardiology (ESC) quality indicators (QIs) for the evaluation of the care and outcomes of adults with heart failure. METHODS AND RESULTS: The Working Group comprised experts in heart failure including members of the ESC Clinical Practice Guidelines Task Force for heart failure, members of the Heart Failure Association, and a patient representative. We followed the ESC methodology for QI development. The 2023 focused guideline update was reviewed to assess the suitability of the recommendations with strongest association with benefit and harm against the ESC criteria for QIs. All the new proposed QIs were individually graded by each panellist via online questionnaires for both validity and feasibility. The existing heart failure QIs also underwent voting to 'keep', 'remove' or 'modify'. Five domains of care for the management of heart failure were identified: (1) structural QIs, (2) patient assessment, (3) initial treatment, (4) therapy optimization, and (5) patient health-related quality of life. In total, 14 'main' and 3 'secondary' QIs were selected across the five domains. CONCLUSION: This document provides an update of the previously published ESC QIs for heart failure to ensure that these measures are aligned with contemporary evidence. The QIs may be used to quantify adherence to clinical practice as recommended in guidelines to improve the care and outcomes of patients with heart failure.

A practical approach to the guideline-directed pharmacological treatment of heart failure with reduced ejection fraction.

Over the last 15-20 years, remarkable developments of heart failure (HF) pharmacotherapies have been achieved. However, HF remains a global healthcare challenge with more than 64 million patients worldwide. Optimization of guideline-directed chronic HF medical therapy is highly recommended with every patient visit to improve outcomes in patients with HF with reduced ejection fraction. However, the majority of patients in real-world settings are treated with doses that are lower than those with proven efficacy in clinical trials, which might be due to concerns of adverse effects and inertia of physicians. Likewise, a significant proportion of patients still do not receive all drug classes that could improve their prognosis. The recent European Society of Cardiology guidelines do not provide detailed recommendations on how these drug classes should be implemented in the treatment of inpatients to allow for both safety and a high likelihood of efficacy. We therefore propose a practical approach algorithm to support physicians to treat HF patients in their daily practice.

Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis.

INTRODUCTION: AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. MATERIAL AND METHODS: We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. RESULTS: FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2 > 50%) between the trials for any of the analyzed outcomes. CONCLUSIONS: Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while effects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.

Impact of the COVID-19 pandemic on implementation of novel guideline-directed medical therapies for heart failure in Germany: a nationwide retrospective analysis.

Background: Guideline-directed medical therapy (GDMT) is the cornerstone in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) and novel substances such as sacubitril/valsartan (S/V) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated marked clinical benefits. We investigated their implementation into real-world HF care in Germany before, during, and after the COVID-19 pandemic period. Methods: The IQVIA LRx data set is based on ∼80% of 73 million people covered by the German statutory health insurance. Prescriptions of S/V were used as a proxy for HFrEF. Time trends were analysed between Q1/2016 and Q2/2023 for prescriptions for S/V alone and in combination therapy with SGLT2i. Findings: The number of patients treated with S/V increased from 5260 in Q1/2016 to 351,262 in Q2/2023. The share of patients with combination therapy grew from 0.6% (29 of 5260) to 14.2% (31,128 of 219,762) in Q2/2021, and then showed a steep surge up to 54.8% (192,429 of 351,262) in Q2/2023, coinciding with the release of the European Society of Cardiology (ESC) guidelines for HF in Q3/2021. Women and patients aged >80 years were treated less often with combined therapy than men and younger patients. With the start of the COVID-19 pandemic, the number of patients with new S/V prescriptions dropped by 17.5% within one quarter, i.e., from 26,855 in Q1/2020 to 22,145 in Q2/2020, and returned to pre-pandemic levels only in Q1/2021. Interpretation: The COVID-19 pandemic was associated with a 12-month deceleration of S/V uptake in Germany. Following the release of the ESC HF guidelines, the combined prescription of S/V and SGLT2i was readily adopted. Further efforts are needed to fully implement GDMT and strengthen the resilience of healthcare systems during public health crises. Funding: Supported by Novartis Pharma GmbH, Nuremberg, Germany.

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

AIMS: In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. METHODS AND RESULTS: The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. CONCLUSION: Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.