Intermittent Levosimendan Research Articles

Case study: de novo vericiguat and intermittent levosimendan on top of optimal medical therapy in advanced heart failure patients as destination therapy

Case study: de novo vericiguat and intermittent levosimendan on top of optimal medical therapy in advanced heart failure patients as destination therapy

Intermittent levosimendan infusions for advanced heart failure: a systematic review and meta-analysis of randomized controlled trials

Abstract Background Intermittent intravenous infusions of levosimendan have been shown to provide benefits in patients with advanced heart failure (AHF), preventing HF rehospitalization and mortality. Purpose We aim to investigate the efficacy of intermittent intravenous levosimendan infusion in patients with AHF. Methods A systematic review and meta-analysis synthesizing evidence from randomized controlled trials (RCTs) obtained from PubMed, Embase Cochrane, Scopus, and WOS until September 2023. We used the random-effects model to report dichotomous outcomes using risk ratio (RR) and continuous outcomes using mean difference (MD), with a 95% confidence interval (CI). Finally, we implemented a trial sequential analysis (TSA) to improve the reliability of our results. Results We included 15 RCTs with 1,181 patients. Intermittent levosimendan was significantly associated with an improved left ventricular ejection fraction (LVEF) compared to placebo (MD: 6,39, 95% CI [3.04, 9.73], P= 0.002; I2=75, P=0.0005), with cumulative Z-score of change after ≤ 1 week passing the monitoring boundaries favors the levosimendan but did not cross the required information size. Additionally, there was a significant improvement in the all-cause mortality rate favoring levosimendan (RR: 0.60, 95% CI [0.40, 0.90], P= 0.01; I2=9, P=0.36). However, There was no difference between intermittent levosimendan and placebo in all-cause rehospitalization rate (RR: 0.75, 95% CI [0.46, 1.22], P= 0.25; I2=70, P=0.04) or event-free survival rate (RR: 0.97, 95% CI [0.72, 1.30], P= 0.84; I2=63, P=0.03). Conclusion In patients with AHF, intermittent levosimendan significantly improved LVEF and all-cause mortality rate. However, there was no effect on rehospitalization or event-free survival.Figure 1.LVEF and TSAFigure 2.Mortality, Rehospital, Surviva

The Efficacy and Safety of Levosimendan in Patients with Advanced Heart Failure: An Updated Meta-Analysis of Randomized Controlled Trials.

Intermittent ambulatory levosimendan administration has been shown in several small randomized controlled trials to benefit patients with advanced heart failure, preventing heart failure rehospitalization and mortality. We aim to investigate the totality of high-quality evidence regarding the efficacy and safety of intermittent levosimendan in advanced heart failure patients. Up to September 2023, we systematically reviewed the randomized controlled trials indexed in PubMed, Embase Cochrane, SCOPUS, and Web of Science. We used mean difference (MD) to estimate the continuous outcomes, and risk ratio (RR) for the dichotomous outcomes with a 95% confidence interval (CI), using the random-effects model. Ultimately, a trial sequential analysis was employed to enhance the reliability of our findings and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework for certainty leveling. Fifteen randomized controlled trials with 1181 patients were included. Intermittent levosimendan was significantly associated with an improved left ventricular ejection fraction compared with placebo (MD 6.39 [95% CI 3.04-9.73], P = 0.002; I2 = 75, P = 0.0005), with cumulative z-score of change after ≤ 1 week passing the monitoring boundaries, favoring the levosimendan, but did not cross the required information size. Additionally, levosimendan reduced the all-cause mortality rate (RR 0.60 [95% CI 0.40-0.90], P = 0.01; I2 = 9, P = 0.36). However, we found no difference between levosimendan and placebo in all-cause rehospitalization rate (RR 0.75 [95% CI 0.46-1.22], P = 0.25; I2 = 70, P = 0.04), event-free survival rate (RR 0.97 [95% CI 0.72-1.30], P = 0.84; I2 = 63, P = 0.03), or any adverse event (RR 1 [95% CI 0.73-1.37], P = 1.00, I2 = 0%, P = 0.70). In patients with advanced heart failure, intermittent levosimendan significantly improved left ventricular ejection fraction, brain natriuretic peptide values, and all-cause mortality rate. Levosimendan use is not associated with a change in rehospitalization or event-free survival. PROSPERO identifier number (CRD42023487838).

Repetitive LevosimenDan infusions fOR patients with advanced chronic heart failure in the vulnerable post-discharge period: the multinational randomized LeoDOR trial

Abstract Background Studies of the repetitive use of intravenous levosimendan suggested a beneficial effect in patients with advanced heart failure (HF). It was the aim of the LeoDOR trial to test the efficacy and safety of intermittent levosimendan therapy in the vulnerable phase following a hospitalization for acute HF. Methods In this multicenter, double-blind, three-armed trial with an enrolment period from 3-2018 to 6-2021, patients with advanced HF were randomized 2:1 at the end of an index hospitalization for acute HF to intermittent levosimendan therapy or placebo for a period of 12 weeks. Levosimendan was administered according to center preference either as 6-hour infusion at a rate of 0.2 mcg/kg/min every 2 weeks, or as 24-hour infusion at a rate of 0.1 mcg/kg/min every 3 weeks. The primary efficacy assessment after 14 weeks was based on a global rank endpoint consisting of three hierarchical groups: Tier 1 = time to death or urgent heart transplantation or implantation of a ventricular assist device; Tier 2 = time to non-fatal HF requiring i.v. vasoactive therapy; Tier 3 = time-averaged proportional change in NTproBNP from baseline to week 14. Results Due to a forced interim interruption of the study as a result of the COVID-19 pandemic, the planned number of patients could not be recruited. The final modified intention-to-treat (mITT) analysis included 145 patients (93 in the combined levosimendan arm, 52 in the placebo arm). Patient characteristics were well balanced between treatment and placebo arms (mean age 69.3±9.7 vs 67.9±10.1, proportion of women 22.6% vs 21.2%, HF-hospitalizations in previous 12 months 1.9±1.4 vs. 1.7±1.1, NTproBNP at baseline 4740 ng/L (IQR 2235 – 9016) vs 5380 ng/L (IQR 2287 – 8204). There were no marked differences regarding HF medication and implanted devices. Compared with placebo, intermittent levosimendan had no significant effect on the primary endpoint (mean rank score 71.8 for the levosimendan group vs 75.1 for the placebo group; p = 0.65). However, there was a strong signal towards a higher incidence of the individual clinical components of the primary endpoint (tier 1 plus tier 2) in the levosimendan group vs the placebo group both after 14 weeks (HR 2.94, 95%CI 1.13–7.70; p = 0.028) and 26 weeks (HR 1.65 95%CI 0.87 – 3.12; p = 0.123). The number of investigator-reported adverse events during and immediately after drug application was 12.4% in the levosimendan group vs 11.8% in the placebo group (p = 0.905). Conclusion Our findings do not support the use of intermittent levosimendan to improve post-hospitalization clinical stability in patients who were recently hospitalized with HF and reduced LVEF. Further studies are warranted to find the correct use of levosimendan in advanced heart failure patients.

P240 PREOPERATIVE OPTIMISATION FOR A PATIENT WITH HEART FAILURE UNDERGOING MAJOR NON–CARDIAC SURGERY: AN EXAMPLE OF COLLABORATION BETWEEN THE MULTIMODAL PREHABILITATION CENTRE AND THE HEART FAILURE CLINIC AT CAREGGI UNIVERSITY HOSPITAL

Abstract Introduction Heart failure (HF) is a risk factor for postoperative mortality in major non–cardiac surgery. Collaboration between the Multimodal Preoperative Prehabilitation unit (MPP) and Heart Failure Clinic (HFC) could allow optimization of heart failure therapy and negative prognostic factors such as reduced functional capacity (FC), malnutrition, and sarcopenia to improve the prognosis of these patients. Case report: Mrs. C.M. is a 58–year–old patient who presents to the MPP unit in anticipation of total colectomy for drug–refractory ulcerative colitis. Mrs. C.M. has a past medical history significant for heart failure with reduced ejection fraction (EF 25%) of presumably valvular–arrhythmic etiology. She underwent tricuspid annuloplasty and mitral replacement surgery some years ago and is affected by atrial fibrillation. At the MPP unit, Mrs. C.M. had a reduced FC and was malnourished and sarcopenic. Blood tests showed iron deficiency anemia. Heart failure therapy (NYHA II) was not optimized according to guidelines. Therefore, the patient started multimodal prehabilitation consisting of aerobic and resistance exercise, nutritional intervention, intravenous iron infusion, and optimization of HF therapy. After the patient was evaluated at the HFC, she started empagliflozin, sacubitril/valsartan, and ranolazine; intermittent levosimendan therapy was also performed. She also underwent cardiac NMR, which showed non–ischemic fibrosis, and coronary angiography, which was negative. Finally, she underwent PM–ICD implantation. After six months of multimodal prehabilitation, there was an increase in EF (38% vs. 25%), a reduction in NT–proBNP (700 vs 4988 pg/mL), and mitigation of HF symptoms. There was also a marked improvement in FC (383 vs 269 meters at 6–minute walking test), nutritional status (stage B vs stage C at PG–SGA test), and muscle strength (handgrip strength test 14.6 vs 8.5 kg). Considering the excellent preoperative optimization response, it was decided to proceed with surgery after a collegial discussion (anesthetist, heart failure cardiologist, surgeon, and patient). Conclusions Multimodal preoperative prehabilitation, based on the collaboration between the Multimodal Preoperative Prehabilitation Unit and Heart Failure Clinic, can effectively improve the preoperative functional capacity of HF patients.

Intermittent inotropic support with levosimendan in advanced heart failure as destination therapy: The LEVO-D registry.

Patients with advanced heart failure (AHF) who are not candidates to advanced therapies have poor prognosis. Some trials have shown that intermittent levosimendan can reduce HF hospitalizations in AHF in the short term. In this real-life registry, we describe the patterns of use, safety and factors related to the response to intermittent levosimendan infusions in AHF patients not candidates to advanced therapies. Multicentre retrospective study of patients diagnosed with advanced heart failure, not HT or LVAD candidates. Patients needed to be on the optimal medical therapy according to their treating physician. Patients with de novo heart failure or who underwent any procedure that could improve prognosis were not included in the registry. Four hundred three patients were included; 77.9% needed at least one admission the year before levosimendan was first administered because of heart failure. Death rate at 1year was 26.8% and median survival was 24.7 [95% CI: 20.4-26.9] months, and 43.7% of patients fulfilled the criteria for being considered a responder lo levosimendan (no death, heart failure admission or unplanned HF visit at 1year after first levosimendan administration). Compared with the year before there was a significant reduction in HF admissions (38.7% vs. 77.9%; P<0.0001), unplanned HF visits (22.7% vs. 43.7%; P<0.0001) or the combined event including deaths (56.3% vs. 81.4%; P<0.0001) during the year after. We created a score that helps predicting the responder status at 1year after levosimendan, resulting in a score summatory of five variables: TEER (+2), treatment with beta-blockers (+1.5), Haemoglobin >12g/dL (+1.5), amiodarone use (-1.5) HF visit 1year before levosimendan (-1.5) and heart rate >70b.p.m. (-2). Patients with a score less than -1 had a very low probability of response (21.5% free of death or HF event at 1year) meanwhile those with a score over 1.5 had the better chance of response (68.4% free of death or HF event at 1year). LEVO-D score performed well in the ROC analysis. In this large real-life series of AHF patients treated with levosimendan as destination therapy, we show a significant decrease of heart failure events during the year after the first administration. The simple LEVO-D Score could be of help when deciding about futile therapy in this population.

Intermittent Levosimendan for Late Right Ventricular Failure in Patients with Left Ventricular Assist Devices

<h3>Purpose</h3> Implantable continuous flow left ventricular assist devices (LVADs) are increasingly used in end-stage heart failure as a bridge-to-transplant (BTT) or destination therapy (DT). One of its most common pitfalls is the development of right ventricular (RV) failure. Despite the fact that right heart failure remains an independent risk factor for mortality, evidence-based therapies are still lacking. The aim of the study is to describe our preliminary single center experience using intermittent infusion of levosimendan in patients with late right heart failure post LVAD implantation. <h3>Methods</h3> We retrospectively revised the data of all patients who received an LVAD in our center and evaluated the patient characteristics and outcomes of those treated with levosimendan for late RV failure. <h3>Results</h3> In the past 10 years (from 2011 until 2020), a total of 130 patients received an LVAD and 8 of them were treated with intermittent levosimendan for RV failure (3 females and 5 males). Two patients had a HeartMate 2 (HM2) and six a HeartMate 3 (HM3). The mean age at LVAD implantation was 59 years and the etiology of their heart failure was coronary artery disease (4/8), myocarditis (2/8) or a non-ischemic dilated cardiomyopathy (2/8). All patients received a monthly dose between 0.1 and 0.3 mcg/kg/min. The average duration of levosimendan therapy during our follow-up was 12 months (ranged from 4 to 26 months). Two patients died because of multi-organ failure due to progression of RV failure, while one of them also suffered hemolysis and several gastrointestinal bleedings. One patient was successfully bridged to a heart transplant (after 13 months of levosimendan therapy), but unfortunately died directly after surgery due to acute graft failure. In one other patient, levosimendan was stopped at the request of the patient based on a subjective lack of efficacy and one episode of ventricular tachycardia. The four remaining patients continue their intermittently therapy and are still alive (2 waiting for the availability of a heart transplant, while the other two have LVAD as destination therapy). <h3>Conclusion</h3> In this first case series, the intermittent use of levosimendan looks promising for the treatment of late RV failure after LVAD.

Efficacy and safety of intermittent repeated levosimendan infusions in advanced heart failure patients: the LAICA study.

AimsThe aim of the LAICA study was to evaluate the long‐term effectiveness and safety of intermittent levosimendan infusion in patients with advanced heart failure (AdHF).Methods and resultsThis was a multicentre, randomized, double‐blind, placebo‐controlled clinical trial of intermittent levosimendan 0.1 μg/kg/min as a continuous 24‐h intravenous infusion administered once monthly for 1 year in patients with AdHF. The primary endpoint [incidence of rehospitalization (admission to the emergency department or hospital ward for >12 h) for acute decompensated HF or clinical deterioration of the underlying HF] occurred in 23/70 (33%) of the levosimendan group (Group I) and 12/27 (44%) of the placebo group (Group II) (P = 0.286). The incidence of hospital readmissions for acute decompensated HF (Group I vs. Group II) at 1, 3, 6, and 12 months was 4.2% vs. 18.2% (P = 0.036); 12.8% vs. 33.3% (P = 0.02); 25.7% vs. 40.7% (P = 0.147); 32.8% vs. 44.4% (P = 0.28), respectively. In a secondary pre‐specified time‐to‐event analysis no differences were observed in admission for acute decompensated HF between patients treated with levosimendan compared with placebo (hazard ratio 0.66; 95% CI, 0.32–1.32; P = 0.24). Cumulative incidence for the aggregated endpoint of acute decompensation of HF and/or death at 1 and 3 months were significatively lower in the levosimendan group than in placebo group [5.7% vs. 25.9% (P = 0.004) and 17.1% vs. 48.1% (P = 0.001), respectively], but not at 6 and 12 months [34.2% vs. 59.2% (P = 0.025); 41.4% vs. 66.6% (P = 0.022), respectively]. Survival probability was significantly higher in patients who received levosimendan compared with those who received placebo (log rank: 4.06; P = 0.044). There were no clinically relevant differences in tolerability between levosimendan and placebo and no new safety signals were observed.ConclusionsIn our study, intermittent levosimendan in patients with AdHF produced a statistically non‐significant reduction in the incidence of hospital readmissions for acute decompensated HF, a significantly lower cumulative incidence of acute decompensation of HF and/or death at 1 and 3 month of treatment and a significant improvement in survival during 12 months of treatment.

Intermittent Levosimendan Infusion in Ambulatory Patients with End-Stage Heart Failure: A Systematic Review and Meta-Analysis

Purpose The safety and efficacy of ambulatory intermittent LEVO infusions in patients with end-stage HF are yet not established. We sought to synthesize the available evidence regarding safety and efficacy of intermittent Levosimendan (LEVO) infusions in ambulatory patients with end-stage heart failure (HF). Methods We systematically searched MEDLINE, EMBASE, SCOPUS, Web of Science and Cochrane databases, from inception to September 27,2019 for studies reporting outcome of adult ambulatory patients with end-stage HF treated with intermittent LEVO infusion. Results Fifteen studies (8 randomized and 7 observational), comprised 984 patients (LEVO[N=727] and controls[N=257]) met the inclusion criteria. LEVO was associated with improved New York Heart Association(NYHA) functional class, (weighted mean difference [WMD] -1.04, 95%CI -1.70 to -0.38, p Conclusion Intermittent Levosimendan infusions in ambulatory patients with end-stage HF is associated with less frequent cardiovascular death alongside with improved NYHA class, quality of life, BNP levels and LV function. However, the current evidence is limited by heterogeneous and relatively small studies.

Intermittent outpatient administration of levosimendan improves right ventricular-pulmonary arterial coupling in ambulatory patients with advanced heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Background Intermittent infusions of levosimendan in an outpatient setting have been associated with improved symptoms and reduced hospitalizations in patients with advanced heart failure (HF). Little is known on the potential effect of intermittent levosimendan infusions on right ventricle (RV)-pulmonary arterial (PA) coupling in ambulatory patients with advanced HF. Purpose Aim of the present study was to explore the effects of intermittent levosimendan infusions on the ratio between tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PAPs), an echocardiographic measure of RV/PA coupling, in ambulatory patients with advanced HF, and on left ventricular arterial coupling (VAC), expressed as the relationship between arterial elastance (Ea) and ventricular elastance (Ees). Methods 17 ambulatory patients with advanced HF treated with intermittent levosimendan (6-hour intravenous infusion, 0.2 ug/kg/min without bolus) received baseline clinical, biochemical and echocardiographic evaluation and changes in TAPSE/PAPs ratio were assessed from baseline to 48 hours after the infusion, based on the pharmacokinetic profile of levosimendan. VAC, expressed as Ea/Ees ratio, was obtained by a calculator (iElastance) designed for non-invasive single beat measure of end-systolic Ees and Ea according to Chen"s method. Results After 48 hours from levosimendan infusion, there was a significant improvement of TAPSE/PAPs ratio (p = 0.04), stroke voume (SV) (p = 0.05) and cardiac output (CO)(p = 0.04). We observed a significant reduction of Ea (p = 0.007) and of Ees (p = 0.01) and a non significant improvement of VAC (p = 0.4)(Tab.1). Conclusion. Our results show that an intermittent 6-hour levosimendan infusion at 0.2 ug/kg/min improves after 48 hours RV-PA coupling, SV, CO, Ea and Ees in ambulatory patients with advanced HF. Further studies including more patients are necessary to confirm these preliminary findings. Tab.1 Baseline 48h afterlevosimendan infusion p value NT-proBNP (pg/mL) 5607 ± 4300 3868 ± 3856 &amp;lt;0.001 LVEF (%) 24.1 ± 7.7 25.7 ± 7.3 0.5 SV (mL) 36.8 ± 12.4 46.1 ± 14.8 0.05 CO (L/min)36.8 ± 12.4 2.6 ± 0.7 3.2 ± 0.9 0.05 TAPSE/PAPs (mm/mmHg) 0.38 ± 0.13 0.49 ± 0.16 0.04 Ea (mmHg/mL/m2) 2.9 ± 0.9 2.1 ± 0.6 0.007 Ees (mmHg/mL/m2) 1.3 ± 0.4 1.0 ± 0.2 0.01 VAC 2.2 ± 0.6 2.0 ± 0.4 0.4

Levosimendan as a bridge to heart transplant in a 16-year-old patient with univentricular heart

We report the successful use of levosimendan in the treatment of heart failure in a patient with the univentricular heart. The presented case was atypical because our patient had systemic right ventricle. To our knowledge, it is the first reported such case with intermittent levosimendan administration as an effective treatment and bridge to successful heart transplant in a patient with functionally univentricular heart.

The use of low-dose intermittent levosimendan infusion therapy as bridge-to-left ventricular assist device in advanced chronic heart failure secondary to isolated cardiac sarcoidosis

Heart failure (HF) is a progressive condition that usually involves a debilitating late course with poor health-related quality of life and increasing mortality rate. In this report, we demonstrate the efficacy and safety of intermittent levosimendan infusion as a bridging therapy to left ventricular assist device use in a patient suffering from cardiac sarcoidosis who failed to respond to optimized medical therapy. Levosimendan was administered in an outpatient infusion-therapy facility every 2 weeks as a single intravenous infusion over 6 h at dose and rate of 0.2 μg/kg/min not proceeded by a bolus. The primary observation we are reporting is the efficacy of this approach reflected on serum concentrations of N-terminal brain natriuretic propeptide and creatinine levels. Secondary observation comprised patient-reported outcomes and clinical events including hospitalization (s).

Is Levosimendan Infusion Useful in Patients with Advanced Heart Failure? Meta-Analysis and Systematic Review

Background: Heart failure is a growing problem with a progressive increase in the number of patients as a result of better treatment outcomes and medical interventions. Patients with advanced heart failure who are not candidates for heart transplantation or left ventricular assist device become a major challenge for the health system, as they have a high mortality and hospitalization rate. Intermittent levosimendan infusion has been used in this group of patients even though the evidence is still controversial. Objective: The purpose of this study is to determine the efficacy of intermittent levosimendan infusion in patients with advanced heart failure. Methods: We conducted a systematic review of the literature on EMBASE, EPISTEMONIKOS, MEDLINE/Pubmed and Trip database until January 2018. We included published randomized clinical trials and meta-analysis without language restriction. Results: Eleven studies including 586 patients evaluating intermittent levosimendan infusions in patients with advanced heart failure were included for evaluation. After a follow up period between 3 and 12 months there was a 55% reduction in mortality Odds Ratio (OR) 0.45 CI 95% (0.26; 0.78. p<0.003), a reduction in natriuretic peptide levels and an improvement in left ventricular ejection fraction without a reduction in hospitalization rates. Conclusions: Intermittent levosimendan infusions in patients with advanced heart failure showed significant benefit in patients with advanced heart failure with mortality reduction becoming a promising alternative in the treatment of this group of patients.

Repetitive levosimendan infusions for patients with advanced chronic heart failure in the vulnerable post-discharge period.

Hospitalization for acute heart failure (HF) is associated with a substantial morbidity burden and with associated healthcare costs and an increased mortality risk. However, few if any major medical innovations have been witnessed in this area in recent times. Levosimendan is a first‐in‐class calcium sensitizer and potassium channel opener indicated for the management of acute HF. Experience in several clinical studies has indicated that administration of intravenous levosimendan in intermittent cycles may reduce hospitalization and mortality rates in patients with advanced HF; however, none of those trials were designed or powered to give conclusive insights into that possibility. This paper describes the rationale and protocol of LeoDOR (levosimendan infusions for patients with advanced chronic heart failure), a randomized, double‐blind, placebo‐controlled, international, multicentre trial that will explore the efficacy and safety of intermittent levosimendan therapy, in addition to optimized standard therapy, in patients following hospitalization for acute HF. Salient features of LeoDOR include the use of two treatment regimens, in order to evaluate the effects of different schedules and doses of levosimendan during a 12 week treatment phase, and the use of a global rank primary endpoint, in which all patients are ranked across three hierarchical groups ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalization and, lastly, time‐averaged proportional change in N‐terminal pro‐brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks.

Intermittent Levosimendan to Maintain Quality of Life in an Ambulatory Patient with End-Stage Heart Failure with Complex Congenital Heart Disease

Intermittent Levosimendan to Maintain Quality of Life in an Ambulatory Patient with End-Stage Heart Failure with Complex Congenital Heart Disease

Rehospitalization after intermittent levosimendan treatment in advanced heart failure patients: a meta-analysis of randomized trials.

AimsIntermittent levosimendan administration has been suggested to improve survival in patients with advanced heart failure (AdHF). Quality of life is a key issue for AdHF patients and is negatively affected by frequent hospitalizations.Methods and resultsCENTRAL, Google Scholar, MEDLINE/PubMed, Scopus, and the Cochrane Central Register of clinical trials (updated 15/1/2017) were searched for randomized controlled trials investigating the effect of intermittent levosimendan administration in patients with AdHF. The primary outcome was the number of patients requiring rehospitalization 3 months after the end of treatment. A total of 319 patients from six trials were included. Overall pooled analysis showed that the use of levosimendan was associated with a significant reduction in the number of rehospitalizations at 3 months: 33/207 (16%) vs. 39/113 (35%), risk ratio 0.40, 95% confidence interval 0.27–0.59, P < 0.001, I 2 = 0%. This result was confirmed by sensitivity analyses.ConclusionsWithin the limitations of this meta‐analysis including also studies in which endpoints were not independently adjudicated and not clearly specified, repetitive or intermittent administration of levosimendan for patients with AdHF was associated with a reduction in the rehospitalization rate at 3 months. Large, high‐quality randomized controlled trials are needed to confirm this finding.

Intermittent levosimendan infusions in advanced heart failure: a real world experience.

ObjectiveTo analyse the effects of levosimendan infusions in advanced heart failure.MethodsPatients with advanced heart failure treated with repeated levosimendan infusions were retrospectively compared with controls. Clinical, blood and echocardiographic parameters were obtained at baseline and after 12 months, and before and after each levosimendan infusion. Hospitalizations for heart failure and in-hospital length of stay in the 6 months before enrolment and after 6 and 12 months were recorded, along with 1-year mortality.ResultsTwenty-five patients treated with levosimendan and 25 controls were studied. After each levosimendan infusion, ventricular function and various clinical and metabolic parameters were improved. After 12 months, left ventricular ejection fraction (LVEF) had improved compared with baseline in the levosimendan group. The 1-year mortality rate was similar in both groups. During the 6 months before enrolment, hospitalizations were fewer in controls compared with the levosimendan group; after 6 and 12 months they increased in controls and decreased in the levosimendan group. Seven patients were super-responders to levosimendan, with LVEF improving more than 20% and hospitalizations being reduced at 12 months compared with the rest of the levosimendan group.ConclusionIntermittent levosimendan improved LVEF and decreased hospitalizations in advanced heart failure and represents a therapeutic option for patients whose disease is worsening.

Long-term intravenous inotropes in low-output terminal heart failure?

Intravenous inotropic therapy may be necessary to achieve short-term survival in end-stage heart failure patients with cardiogenic shock or extreme low output and severe organ hypoperfusion. However, mid- or long-term intravenous inotropic therapy is associated with an increased mortality in advanced stage D heart failure patients using β-adrenoceptor agonists (dobutamine) or PDE-3-inhibitors (milrinone). Intermittent levosimendan may evolve as a reasonable therapeutic option. Randomized trials or other meaningful scientific evidence addressing the optimal treatment of exclusively the most threatened subgroup of hospitalized patients with persistent severe organ hypoperfusion are missing, but urgently needed. Despite a lack of other beneficial pharmacological options, the use of long-term intravenous inotropic therapy as a treatment for refractory heart failure or as an obligatory criterion for high urgency (HU) listing of heart transplant candidates with a median waiting time of 66days in Germany is not based on scientific evidence. In addition, it might create a disincentive to achieve the HU status as well as keeping it, thereby potentially exposing the patient to an unnecessary additional risk. Upcoming new allocation algorithms may possibly help to improve the inadequate present situation. There is need for both, a better definition and a better treatment of high risk terminal heart failure requiring high urgent transplant listing.

Repeated or intermittent levosimendan treatment in advanced heart failure: An updated meta-analysis

IntroductionAdvanced heart failure is a malignant disease characterized by a debilitating late course, with increasingly frequent hospitalisations and high rate of mortality.Levosimendan, an inodilator developed for the treatment of acutely decompensated chronic heart failure, has been recently proposed also as a repetitive treatment of advanced heart failure.Several studies on the use of levosimendan in this settings report mortality data. Independent meta-analyses on the effect on mortality of repetitive or intermittent levosimendan administration in advanced heart failure has been published but were criticized in regard to the selection of the studies. Meanwhile new data became available. We therefore updated the selection of studies and re-analyzed all the available data. Methods & resultsData from seven randomized trial and a total of 438 adult patients using intermittent levosimendan in a cardiological setting were included in the present analysis. The average follow-up period was 8±3.8months. The use of levosimendan was associated with a significant reduction in mortality at the longest follow-up available [41 of 257 (16%) in the levosimendan group vs. 39 of 181 (21.5%) in the control arm, OR=0.54 (95% CI 0.32–0.91), p for effect=0.02, p for heterogeneity=0.64, I2=0%]. ConclusionsThe updated results suggest that repetitive or intermittent levosimendan administration in advanced heart failure is associated with a significant reduction in mortality at the longest follow-up available. There is therefore a strong rationale for a randomized clinical trial with adequate power on mortality.

Clinical trials update from the European Society of Cardiology-Heart Failure meeting 2015: AUGMENT-HF, TITRATION, STOP-HF, HARMONIZE, LION HEART, MOOD-HF, and renin-angiotensin inhibitors in patients with heart and renal failure.

This article provides an overview on the key trials relevant to the pathophysiology, prevention, and treatment of heart failure (HF) presented at the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) annual meeting held in Seville, Spain in May 2015. Trials reported include AUGMENT-AF (myocardial injections of calcium-alginate hydrogel), a propensity score-matched study of renin-angiotensin system antagonists in patients with HF and severe renal dysfunction, HARMONIZE (sodium zirconium cyclosilicate used to bind potassium), TITRATION, comparing two regimes for introducing LCZ696, STOP-HF, a trial of intramyocardial stromal cell-derived factor-1, MOOD-HF (escitalopram for patients with heart failure and depression), and LION HEART, a trial of intermittent levosimendan therapy. Unpublished reports should be considered as preliminary, since analyses may change in the final publication.