Navigating between Scylla and Charybdis: challenges and strategies for implementing guideline-directed medical therapy in heart failure with reduced ejection fraction.

Guideline-directed medical therapy (GDMT) has the potential to reduce the risks of mortality and hospitalisation in patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, real-world data indicate that many patients with HFrEF do not receive optimised GDMT, which involves several different medications, many of which require up-titration to target doses. There are many challenges to implementing GDMT, the most important being patient-related factors (comorbidities, advanced age, frailty, cognitive impairment, poor adherence, low socioeconomic status), treatment-related factors (intolerance, side-effects) and healthcare-related factors that influence availability and accessibility of HF care. Accordingly, international disparities in resources for HF management and limited public reimbursement of GDMT, coupled with clinical inertia for treatment intensification combine to hinder efforts to provide GDMT. In this review paper, authors aim to provide solutions based on available evidence, practical experience, and expert consensus on how to utilise evolving strategies, novel medications, and patient profiling to allow the more comprehensive uptake of GDMT. Authors discuss professional education, motivation, and training, as well as patient empowerment for self-care as important tools to overcome clinical inertia and boost GDMT implementation. We provide evidence on how multidisciplinary care and institutional accreditation can be successfully used to increase prescription rates and adherence to GDMT. We consider the role of modern technologies in advancing professional and patient education and facilitating patient-provider communication. Finally, authors emphasise the role of novel drugs (especially sodium-glucose co-transporter 2 inhibitors), and a tailored approach to drug management as evolving strategies for the more successful implementation of GDMT.

Serum uric acid and outcomes in patients with chronic heart failure through the whole spectrum of ejection fraction phenotypes: Analysis of the ESC-EORP Heart Failure Long-Term (HF LT) Registry.

BACKGROUND: Retrospective analyses of clinical trials indicate that elevated serum uric acid (sUA) predicts poor outcome in heart failure (HF). Uric acid can contribute to inflammation and microvascular dysfunction, which may differently affect different left ventricular ejection fraction (LVEF) phenotypes. However, role of sUA across LVEF phenotypes is unknown. OBJECTIVES: We investigated sUA association with outcome in a prospective cohort of HF patients stratified according to LVEF. METHODS: Through the Heart Failure Long-Term Registry of the European Society of Cardiology (ESC-EORP-HF-LT), 4,438 outpatients were identified and classified into: reduced (<40% HFrEF), mid-range (40-49% HFmrEF), and preserved (≥50% HFpEF) LVEF. Endpoints were the composite of cardiovascular death/HF hospitalization, and individual components. RESULTS: Median sUA was 6.72 (IQ:5.48-8.20) mg/dl in HFrEF, 6.41 (5.02-7.77) in HFmrEF, and 6.30 (5.20-7.70) in HFpEF. At a median 372-day follow-up, the composite endpoint occurred in 648 (13.1%) patients, with 176 (3.6%) deaths and 538 (10.9%) HF hospitalizations. Compared with lowest sUA quartile (Q), Q-III and Q-IV were significantly associated with the composite endpoint (adjusted HR 1.68: 95% CI 1.11-2.54; 2.46: 95% CI 1.66-3.64, respectively). By univariable analyses, HFrEF and HFmrEF patients in Q-III and Q-IV, and HFpEF patients in Q-IV, showed increased risk for the composite endpoint (P<0.05 for all); after model-adjustment, significant association of sUA with outcome persisted among HFrEF in Q-IV, and HFpEF in Q-III-IV. CONCLUSIONS: In a large, contemporary-treated cohort of HF outpatients, sUA is an independent prognosticator of adverse outcome, which can be appreciated in HErEF and HFpEF patients.

Patient perceptions of anticoagulant treatment with dabigatran or a vitamin K antagonist for stroke prevention in atrial fibrillation according to region and age: an exploratory analysis from the RE-SONANCE study.

BACKGROUND: The oral anticoagulant dabigatran offers an effective alternative to vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF), yet patient preference data are limited. The prospective observational RE-SONANCE study demonstrated that patients with AF, newly initiated on dabigatran, or switching to dabigatran from long-term VKA therapy, reported improved treatment convenience and satisfaction compared with VKA therapy. This pre-specified sub-study aimed to assess the impact of country and age on patients' perceptions of dabigatran or VKA therapy in AF. METHODS: RE-SONANCE was an observational, prospective, multi-national study (NCT02684981) that assessed treatment satisfaction and convenience in patients switching from VKAs to dabigatran (Cohort A), or newly diagnosed with AF receiving dabigatran or VKAs (Cohort B), using the PACT-Q questionnaire. Pre-specified exploratory outcomes: variation in PACT-Q2 scores by country and age (< 65, 65 to < 75, ≥ 75 years) (both cohorts); variation in PACT-Q1 responses at baseline by country and age (Cohort B). RESULTS: Patients from 12 countries (Europe/Israel) were enrolled in Cohort A (n = 4103) or B (n = 5369). In Cohort A, mean (standard deviation) PACT-Q2 score increase was highest in Romania (convenience: 29.6 [23.6]) and Hungary (satisfaction: 26.0 [21.4]) (p < 0.001). In Cohort B, mean (standard error) increase in PACT-Q2 scores between dabigatran and VKAs was highest in Romania (visit 3: 29.0 [1.3]; 24.5 [0.9], p < 0.001). Mean PACT-Q2 score increase by age (all p < 0.001) was similar across ages. PACT-Q1 responses revealed lowest expectations of treatment success in Romania and greatest concerns about payment in Estonia, Latvia, and Romania, but were similar across ages. CONCLUSIONS: Treatment satisfaction and convenience tended to favor dabigatran over VKAs. Regional differences in treatment expectations exist across Europe. TRIAL AND CLINICAL REGISTRY: Trial registration number: ClinicalTrials.gov NCT02684981. Trial registration date: February 18, 2016.

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.

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

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation 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 heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac 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, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years.

Patient perception of anticoagulant treatment for stroke prevention (RE-SONANCE study).

Objective: We evaluated atrial fibrillation (AF) patients' perceptions of anticoagulation treatment with dabigatran or a vitamin K antagonist (VKA) for stroke prevention, according to accepted indications. Methods: The RE-SONANCE observational, prospective, multicentre, international study used the validated Perception on Anticoagulant Treatment Questionnaire (PACT-Q) to assess patients with AF already taking a VKA who were switched to dabigatran (cohort A), and newly diagnosed patients initiated on either dabigatran or a VKA (cohort B). Visit 1 (V1) was at baseline, and visit 2 (V2) and visit 3 (V3) were at 30-45 and 150-210 days after baseline, respectively. Primary outcomes were treatment satisfaction and convenience in cohort A at V2 and V3 versus baseline, and in cohort B for dabigatran and a VKA at V2 and V3. Results: The main analysis set comprised 4100 patients in cohort A and 5365 in cohort B (dabigatran: 3179; VKA: 2186). In cohort A, PACT-Q2 improved significantly (p<0.001 for all) for treatment convenience (mean change V1 vs V2=20.72; SD=21.50; V1 vs V3=24.54; SD=22.85) and treatment satisfaction (mean change V1 vs V2=17.60; SD=18.76; V1 vs V3=21.04; SD=20.24). In cohort B, mean PACT-Q2 scores at V2 and V3 were significantly higher (p<0.001 for all) for dabigatran versus a VKA for treatment convenience (V2=18.38; SE =0.51; V3=23.34; SE=0.51) and satisfaction (V2=15.88; SE=0.39; V3=19.01; SE=0.41). Conclusions: Switching to dabigatran from long-term VKA therapy or newly initiated dabigatran is associated with improved patient treatment convenience and satisfaction compared with VKA therapy.

Short-Term Therapies for Treatment of Acute and Advanced Heart Failure-Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but-per definition-causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio- and vasoactive drugs used in the hospitalization phase to stabilize the patient's hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g. catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents.

A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: An expert panel consensus.

Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remain challenging. The present consensus, derived by a panel meeting of experts from 21 countries, aims at addressing this very issue in the setting of both acute and advanced heart failure.

The role of levosimendan in acute heart failure complicating acute coronary syndrome: A review and expert consensus opinion.

Acute heart failure and/or cardiogenic shock are frequently triggered by ischemic coronary events. Yet, there is a paucity of randomized data on the management of patients with heart failure complicating acute coronary syndrome, as acute coronary syndrome and cardiogenic shock have frequently been defined as exclusion criteria in trials and registries. As a consequence, guideline recommendations are mostly driven by observational studies, even though these patients have a particularly poor prognosis compared to heart failure patients without signs of coronary artery disease. In acute heart failure, and especially in cardiogenic shock related to ischemic conditions, vasopressors and inotropes are used. However, both pathophysiological considerations and available clinical data suggest that these treatments may have disadvantageous effects. The inodilator levosimendan offers potential benefits due to a range of distinct effects including positive inotropy, restoration of ventriculo-arterial coupling, increases in tissue perfusion, and anti-stunning and anti-inflammatory effects. In clinical trials levosimendan improves symptoms, cardiac function, hemodynamics, and end-organ function. Adverse effects are generally less common than with other inotropic and vasoactive therapies, with the notable exception of hypotension. The decision to use levosimendan, in terms of timing and dosing, is influenced by the presence of pulmonary congestion, and blood pressure measurements. Levosimendan should be preferred over adrenergic inotropes as a first line therapy for all ACS-AHF patients who are under beta-blockade and/or when urinary output is insufficient after diuretics. Levosimendan can be used alone or in combination with other inotropic or vasopressor agents, but requires monitoring due to the risk of hypotension.

Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure.

AIMS: The aim of this study was to assess the prevalence of abnormal liver function tests (LFTs) and the associated clinical profile and outcome(s) in acute decompensated heart failure (ADHF) patients. Alteration in LFTs is a recognized feature of ADHF, but prevalence and outcomes data from a broad contemporary cohort of ADHF are scarce and the mechanism(s) of ADHF-induced cholestasis is unknown. METHODS AND RESULTS: We conducted a post hoc analysis of SURVIVE, a large clinical trial including ADHF patients treated with levosimendan or dobutamine. All LFTs were available in 1134 patients at baseline. Abnormal LFTs were seen in 46% of ADHF patients: isolated abnormal alkaline phosphatase (AP) was noted in 11%, isolated abnormal transaminases in 26%, and a combination of abnormal AP and transaminases in 9%. Abnormal AP was associated with marked signs of systemic congestion and elevated right-sided filling pressure. Abnormal AP had no relationship with 31-day mortality but was associated with worse 180-day mortality (23.5 vs. 34.9%, P = 0.001 vs. patients with normal AP). Abnormal transaminases were associated with clinical signs of hypoperfusion and with greater 31-day and 180-day mortality compared with normal transaminase profiles (17.6 vs. 8.4% and 31.6 vs. 22.4%, respectively; both P < 0.001). There was no additive value of abnormal AP plus abnormal transaminase on a long-term outcome. CONCLUSION: Abnormal LFTs were present in about a half of patients presenting with ADHF treated with inotropes. Abnormal AP and abnormal transaminases were associated with specific clinical, biological, and prognostic features, including a short-term overmortality with increased transaminases but not with biological signs of cholestasis, in ADHF patients.

Oral levosimendan in patients with severe chronic heart failure --the PERSIST study.

BACKGROUND: Intravenous levosimendan improves symptoms in acutely decompensated heart failure. AIMS: To evaluate the effects of oral levosimendan in severe chronic heart failure (CHF). METHODS: 307 patients with NYHA IIIB-IV CHF were randomly assigned, double-blind, to levosimendan 1 mg once or twice daily or placebo for at least 180 days. An exploratory primary end-point, the Patient Journey, a composite consisting of repeated symptom assessments, worsening heart failure and mortality during 60 days was used. Minnesota Living with Heart Failure quality of life score (MLHFQoL) and NT-proBNP were assessed repeatedly. RESULTS: Patients assigned to a lower dose of levosimendan had more severe CHF at baseline. No differences in symptoms emerged and worsening heart failure events and death were similar resulting in a similar Patient Journey score with levosimendan and placebo (p=0.567). Compared to placebo, a net improvement of 3-4 points in MLHFQoL at several time-points in favour of the combined levosimendan groups was observed (p<0.001) which was accompanied by a substantial and persistent reduction in NT-proBNP (-30-40%) (p<0.001). CONCLUSION: Levosimendan improved QoL and decreased NT-proBNP but did not improve the Patient Journey composite in patients with severe CHF. Further research with this compound is warranted to clarify safety and efficacy.

Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial.

CONTEXT: Because acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival. OBJECTIVE: To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival. DESIGN, SETTING, AND PATIENTS: The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004. INTERVENTIONS: Intravenous levosimendan (n = 664) or intravenous dobutamine (n = 663). MAIN OUTCOME MEASURE: All-cause mortality at 180 days. RESULTS: All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P = .40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P<.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group. CONCLUSION: Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00348504.

The utility of levosimendan in the treatment of heart failure.

Calcium sensitizers are a new group of inotropic drugs. Levosimendan is the only calcium sensitizer in clinical use in Europe. Its mechanism of action includes both calcium sensitization of contractile proteins and the opening of adenosine triphosphate (ATP)-dependent potassium channels as mechanism of vasodilation. The combination of K-channel opening with positive inotropy offers potential benefits in comparison to currently available intravenous inotropes, since K-channel opening protects myocardium during ischemia. Due to the calcium-dependent binding of levosimendan to troponin C, the drug increases contractility without negative lusitropic effects. In patients with heart failure levosimendan dose-dependently increases cardiac output and reduces pulmonary capillary wedge pressure. Since levosimendan has an active metabolite OR-1896 with a half-life of some 80 hours, the duration of the hemodynamic effects significantly exceeds the 1-hour half-life of the parent compound. The hemodynamic effects of the levosimendan support its use in acute and postoperative heart failure. Several moderate-size trials (LIDO, RUSSLAN, CASINO) have previously suggested that the drug might even improve the prognosis of patients with decompensated heart failure. These trials were carried out in patients with high filling pressures. Recently two larger trials (SURVIVE and REVIVE) in patients who were hospitalized because of worsening heart failure have been finalized. These trials did not require filling pressures to be measured. The two trials showed that levosimendan improves the symptoms of heart failure, but does not improve survival. The results raise the question whether a 24-hour levosimendan infusion can be used without invasive hemodynamic monitoring.

Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study.

The objective of this study was to explore the pharmacodynamics and pharmacokinetics of oral levosimendan in patients with severe congestive heart failure. This was a randomized, parallel-group, double-blind, placebo-controlled trial. Oral levosimendan 2 to 8 mg daily or placebo was administered to 25 patients with New York Heart Association class III-IV congestive heart failure for 4 weeks. Pharmacodynamic variables consisted of heart rate-corrected electromechanical systole, heart rate, and systolic and diastolic blood pressure. The pharmacokinetics of levosimendan and its metabolites, OR-1855 and OR-1896, was assessed. The 4- to 8-mg daily doses of oral levosimendan showed moderate inotropic effects. Blood pressure remained unchanged with all doses. A moderate increase in heart rate was observed except with the 2-mg dose. Pharmacokinetic parameters of the metabolites increased linearly with the dose (P < or = .002 for Cmax and AUC0-8h for both treatment groups). It was concluded that oral levosimendan has inotropic and chronotropic effects in patients with severe congestive heart failure. Plasma concentrations of its metabolites increase dose dependently.

Pharmacodynamic interactions of levosimendan and felodipine in patients with coronary heart disease.

OBJECTIVE: The aim was to study the pharmacodynamic interactions and safety of the co-administration of the calcium sensitizer levosimendan and the calcium antagonist felodipine in patients with coronary heart disease (CHD) and with normal ejection fraction (EF). METHODS: The study was a randomized, double blind, placebo-controlled, crossover study in 24 male patients with Canadian Cardiovascular Society (CCS) class II CHD, consisting of four treatment periods, each period lasting for 7-10 days. In the first period the patients received either oral levosimendan (LS) (0.5 mg) or placebo (PL) four times daily and were then crossed over to the other therapy for the second and third period. After the third period the patients were changed back to the therapy administered in the first period. Open label felodipine (FD), 5 mg once daily, was co-administered on the third and fourth treatment period. Differences between the four treatments (LS, PL, FD and LS + FD) in systolic time intervals, exercise capacity, heart rate, blood pressure and 24-hour continuous electrocardiography (Holter) were assessed. RESULTS: The differences between treatments regarding heart rate corrected electromechanical systole (QS2i), pre-ejection period (PEP) and heart rate corrected left ventricular ejection time (LVETi) were significant (p < 0.001, p < 0.001 and p = 0.004, respectively). Levosimendan shortened QS2i by 10 ms (95% CI [-15, -4]), PEP by 6 ms (95% CI [-10, -3]) and LVETi by 7 ms (95% CI [-13, -2]) compared with placebo, indicating a moderate positive inotropic effect. The results were similar, when levosimendan was administered concomitantly with felodipine. Levosimendan did not significantly change systolic blood pressure and no potentiation of response was seen with concomitant administration with felodipine. The increase in heart rate after levosimendan and its combination with felodipine was equal (6-7 bpm). There was no difference in mean cumulative exercise time between the treatments. The combination of levosimendan and felodipine was well tolerated. CONCLUSION: No clinically significant pharmacodynamic interactions between levosimendan and felodipine were seen. Levosimendan did not aggravate myocardial ischemia. Levosimendan can safely be administered to patients with CHD together with a dihydropyridine calcium antagonist.