Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction.

BACKGROUND: Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed. METHODS: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed. RESULTS: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia. CONCLUSIONS: In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.).

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial.

AIM: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Sleep-disordered breathing patterns in hospitalized patients with acute heart failure across the entire spectrum of ejection fraction.

BACKGROUND: Sleep-disordered breathing (SDB) is prevalent in heart failure (HF). Yet, scarce data exist on sleep-patterns in acute HF and differences in specific subgroups. Our goal was to assess SDB prevalence in hospitalized patients with decompensated HF across the entire spectrum of left ventricle ejection fraction (LVEF). METHODS: Single-center retrospective study enrolling patients admitted for acute HF between 2013 and 2018. All patients were screened for SDB with an ApneaLink™ Plus device before discharge while euvolemic and receiving oral therapy. Those with a sleep study time < 3 h were excluded. HF with reduced, moderately reduced, and preserved LVEF (HFrEF, HFmrEF, and HFpEF) was defined by a LVEF < 40%, 40-49%, and ≥ 50%, respectively. SDB was defined by an apnea-hypopnea index (AHI) ≥ 5/h. RESULTS: Overall, 221 patients were included (mean age 75 ± 11 years). Seventy-two (33%) had HFrEF, 26 (11%) HFmrEF, and 123 (56%) HFpEF. In total, 176 (80%) met the criteria for mild SDB, while 59% and 38% had an AHI ≥ 15/h or ≥ 30/h, respectively. SDB prevalence was high and similar between HFrEF, HFmrEF, and HFpEF. Yet, SDB was often more severe in HFrEF when compared to HFpEF. HFmrEF had intermediate characteristics, with an AHI closer to HFrEF. CONCLUSION: In a cohort of patients admitted for acute HF, SDB was highly prevalent in all subgroups, including HFmrEF. The pervasiveness and severity of SDB was particularly noted in HFrEF. These findings suggest that routine SDB screening may be warranted following acute HF.

Survival and quality of life after early discharge in low-risk pulmonary embolism.

INTRODUCTION: Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes. METHODS: The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism. RESULTS: The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of -9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001). CONCLUSIONS: Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.

Management of RAASi-associated hyperkalemia in patients with cardiovascular disease.

Renin-angiotensin-aldosterone system inhibitors (RAASi) reduce morbidity and mortality in heart failure (HF) with reduced ejection fraction in a dose-dependent manner. They also have a positive impact in other cardiovascular diseases (CVDs). However, RAASi may induce hyperkalemia, a potentially life-threatening disorder. This risk is further increased in those with concomitant chronic kidney disease, diabetes mellitus, and/or in patients with hypertension. Current treatment guidelines recommend maximal RAASi dosing to improve clinical outcomes; however, this is often limited by the development of hyperkalemia. When this occurs, current guidelines recommend RAASi down-titration/interruption, which, while improving short-term prognosis, is associated with a negative long-term prognostic impact. At present, the European Society of Cardiology suggests the consideration of novel potassium binders (patiromer and sodium zirconium cyclosilicate) for the management of RAASi-associated hyperkalemia. Both drugs can reduce serum potassium levels and prevent recurrent hyperkalemia. Additionally, patiromer showed enabling of RAASi optimization in high-risk patients. Nevertheless, precise recommendations on the use of these drugs are lacking. Building upon current HF guideline recommendations, a multidisciplinary expert panel convened to design an algorithm providing practical guidance on the use of novel potassium binders/patiromer in patients with HF and/or other CVD. As a result of that effort, we present an evidence-based treatment algorithm for the management of hyperkalemia with novel potassium binders/patiromer in patients with HF and/or other CVD receiving RAASi, including the necessary monitoring to avoid induction of hypokalemia. This algorithm aims to maintain or up-titrate RAASi to optimized doses, while maintaining normokalemia, improved clinical outcomes, and long-term prognosis.

Dapagliflozin in a Real-World Chronic Heart Failure Population: How Many Are Actually Eligible?

BACKGROUND: In patients with heart failure (HF) and reduced ejection fraction (HFrEF) with or without type 2 diabetes mellitus, the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin was recently shown to reduce the risk of worsening HF or death from cardiovascular causes in the dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF) trial. Our goal was to investigate how many patients in a real-world setting would be eligible for dapagliflozin according to the DAPA-HF enrolment criteria. METHODS: This is a single-center retrospective study enrolling consecutive, unselected patients followed up in an HF clinic from 2013 to 2019. Key DAPA-HF inclusion criteria (i.e., left ventricular ejection fraction [LVEF] ≤40% and NT-proBNP ≥600 pg/mL [or ≥900 pg/mL if atrial fibrillation]) and exclusion criteria (estimated glomerular filtration rate [eGFR] <30 mL/kg/1.73 m2 and systolic blood pressure [SBP] <95 mm Hg) were considered. RESULTS: Overall, 479 patients (age 76 ± 13 years; 50.5% male; 78.9% hypertensive; 45.1% with an eGFR <60 mL/min/1.73 m2; 36.5% with TD2M; and 33.5% with ischaemic HF) were assessed. The median SBP was 128.5 (112.0-146.0) mm Hg, mean eGFR was 50.8 ± 23.7 mL/min/1.73 m2, and median NT-proBNP was 2,183 (IQR 1,010-5,310) pg/mL. Overall, 155 (32.4%) patients had LVEF ≤40%. According to the DAPA-HF trial key criteria, 90 patients (18.8%) would be eligible for dapagliflozin. The remainder would be excluded due to LVEF >40% (67.6%), eGFR <30 mL/min/1.73 m2 (19.4%), NT-proBNP below the cutoff (16.7%), and/or SBP <95 mm Hg (6.5%). If we center the analysis to those with LVEF ≤40%, 58.1% would be eligible for dapagliflozin. The remainder would be excluded due to an eGFR <30 mL/min/1.73 m2 (20%), NT-proBNP below the cutoff (16.1%), and/or SBP <95 mm Hg (8.4%). CONCLUSION: Roughly half of our real-world HFrEF cohort would be eligible for dapagliflozin according to the key criteria of the DAPA-HF trial. The main reason for non-eligibility was an eGFR <30 mL/min/1.73 m2. However, two-thirds of patients had LVEF >40%. These findings show that dapagliflozin is a promising complementary new drug in the therapeutic armamentarium of most patients with HFrEF, while highlighting the urgent need for disease-modifying drugs in mid-range and preserved LVEF and the need to assess the efficacy and safety of SLGT2i in advanced kidney disease patients. The results of ongoing SGLT2i trials in these LVEF subgroups are eagerly awaited.

Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor rivaroxaban: an international multicentre single-arm clinical trial.

AIMS: To investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE, using the oral factor Xa inhibitor rivaroxaban. METHODS AND RESULTS: We conducted a prospective multicentre single-arm investigator initiated and academically sponsored management trial in patients with acute low-risk PE (EudraCT Identifier 2013-001657-28). Eligibility criteria included absence of (i) haemodynamic instability, (ii) right ventricular dysfunction or intracardiac thrombi, and (iii) serious comorbidities. Up to two nights of hospital stay were permitted. Rivaroxaban was given at the approved dose for PE for ≥3 months. The primary outcome was symptomatic recurrent venous thromboembolism (VTE) or PE-related death within 3 months of enrolment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α = 0.004 (<6 primary outcome events). From May 2014 through June 2018, consecutive patients were enrolled in seven countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval 2.1%) suffered symptomatic non-fatal VTE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial. Major bleeding occurred in 6 (1.2%) of the 519 patients comprising the safety population. There were two cancer-related deaths (0.4%). CONCLUSION: Early discharge and home treatment with rivaroxaban is effective and safe in carefully selected patients with acute low-risk PE. The results of the present trial support the selection of appropriate patients for ambulatory treatment of PE.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Sodium-Glucose Co-transporter 2 Inhibitors in the Failing Heart: a Growing Potential.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new drug class designed to treat patients with type 2 diabetes (T2D). However, cardiovascular outcome trials showed that SGLT2i also offer protection against heart failure (HF)-related events and cardiovascular mortality. These benefits appear to be independent of glycaemic control and have recently been demonstrated in the HF population with reduced ejection fraction (HFrEF), with or without T2D. This comprehensive, evidence-based review focuses on the published studies concerning HF outcomes with SGLT2i, discussing issues that may underlie the different results, along with the impact of these new drugs in clinical practice. The potential translational mechanisms behind SGLT2i cardio-renal benefits and the information that ongoing studies may add to the already existing body of evidence are also reviewed. Finally, we focus on practical management issues regarding SGLT2i use in association with other T2D and HFrEF common pharmacological therapies. Safety considerations are also highlighted. Considering the paradigm shift in T2D management, from a focus on glycaemic control to a broader approach on cardiovascular protection and event reduction, including the potential for wide SGLT2i implementation in HF patients, with or without T2D, we are facing a promising time for major changes in the global management of cardiovascular disease.