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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 ( 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 p p 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.

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 potentation 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.

Aims To evaluate the safety and efficacy of levosimendan in patients with left ventricular failure complicating acute myocardial infarction. Methods and Results Levosimendan at different doses (0·1–0·4μg.kg−1.min−1) or placebo were administered intravenously for 6h to 504 patients in a randomised, placebo-controlled, double-blind study. The primary end-point was hypotension or myocardial ischaemia of clinical significance adjudicated by an independent Safety Committee. Secondary end-points included risk of death and worsening heart failure, symptoms of heart failure and all-cause mortality. The incidence of ischaemia and/or hypotension was similar in all treatment groups ( P =0·319). A higher frequency of ischaemia and/or hypotension was only seen in the highest levosimendan dose group. Levosimendan-treated patients experienced lower risk of death and worsening heart failure than patients receiving placebo, during both the 6h infusion (2·0% vs 5·9%; P =0·033) and over 24h (4·0% vs 8·8%; P =0·044). Mortality was lower with levosimendan compared with placebo at 14 days (11·7% vs 19·6%; hazard ratio 0·56 [95% CI 0·33–0·95]; P =0·031) and the reduction was maintained at the 180-day retrospective follow-up (22·6% vs 31·4%; 0·67 [0·45-1·00], P =0·053). Conclusions Levosimendan at doses 0·1–0·2μg.kg−1.min−1 did not induce hypotension or ischaemia and reduced the risk of worsening heart failure and death in patients with left ventricular failure complicating acute myocardial infarction. Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved .

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 (pb0.001) which was accompanied by a substantial and persistent reduction in NT-proBNP (−30–40%) (pb0.001). 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. © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

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.

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 (Por = .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.

ContextBecause 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.ObjectiveTo assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival.Design, Setting, and PatientsThe 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.InterventionsIntravenous levosimendan (n = 664) or intravenous dobutamine (n = 663).Main Outcome MeasureAll-cause mortality at 180 days.ResultsAll-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

Acutely decompensated heart failure (ADHF) represents the most severe form of heart failure with a short-term mortality approaching 30%. The SURVIVE study is the first prospective, randomised trial utilising mortality as the primary variable in evaluating the efficacy of intravenous drug therapy in ADHF. Levosimendan (LS) is a new calcium sensitiser for the treatment of ADHF. Previous studies with LS have shown decreased mortality in comparison with placebo or dobutamine (DB). The studies have, however, not been powered for mortality. A suspicion of detrimental mortality effect of DB has also been raised, but it has not been proven in any sufficiently powered single study or meta-analysis. Therefore, DB is still the most widely used intravenous (IV) inotropic agent in the treatment of ADHF. The SURVIVE study is a multicentre, parallel-group, randomised, double-blind, double-dummy study in patients with ADHF comparing the efficacy of LS with that of DB. The SURVIVE study includes hospitalised patients with ADHF, left ventricular ejection fraction ≤ 30% and clinical need for IV inotropic support. The primary endpoint of the study is all-cause mortality during 180 days following randomisation. Patients will receive two simultaneous intravenous infusions, 'LS/placebo' with a maximum duration of 24 hours and 'DB/placebo' according to clinical judgement (but minimally for 24 hours and starting with a dose of 5 μg/kg/min). During the 180-day period, the originally randomised study drug can be re-administered when clinically justified. Altogether 700 patients will be recruited. The sample size is based on assuming 30% 180-day mortality in the DB group, 33% relative risk reduction in the LS group, with a power of 85% and an alpha-level of 0.05. The study is ongoing in eight countries (Finland, France, Germany, Israel, Latvia, Poland, Russia and UK). After 450 patients have been followed for 1 month or after 90 deaths have occurred, the Data and Safety Monitoring Board will make a recommendation on the continuation/discontinuation of the study following pre-specified stopping rules. Separately, the Steering Committee follows the mortality rate without opening the treatment code and may recommend increasing the sample size. SURVIVE thus represents the first study with two ambitious goals in ADHF: (1) to study a new drug against the accepted reference treatment, DB; (2) to assess mortality. In future, other trials will probably have to follow this new standard of design in this setting.