4 November 2019

November 2019 post

In a recent expert opinion paper by Farmakis et al., published on Int J Cardiol (doi: 10.1016/j.ijcard.2019.09.005; PMID: 31615650) the authors summarized the proceedings of a meeting organized by the Heart Failure Clinic, Attikon University Hospital, Athens, Greece on the topic “A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure”.

Experts from 21 countries (Austria, Belgium, Croatia, Cyprus, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Poland, Russia, Slovenia, Spain, Sweden, Switzerland, and Turkey) attended and reached a consensus

In a nutshell, inotropes increase cardiac output by enhancing cardiac contractility through different mechanisms of action, but they also bear variable vasodilatory or vasoconstrictive effects depending on agent and dosage. They constitute an important tool for the treatment of patients with acute heart failure (AHF) or advanced heart failure (AdHF), as they are often effective in improving hemodynamics and symptoms. However, their administration has been associated with increased short and long-term mortality due to frequent adverse effects, but also due to their improper use. The classes of inotropes currently used in HF are the β-adrenergic receptor agonists including dopamine, dobutamine and the catecholamines norepinephrine and epinephrine, the PDE III inhibitor milrinone and the calcium sensitizer levosimendan.

In AHF, inotropes are indicated with a IIb recommendation by the ESC guidelines only for patients with peripheral hypoperfusion because of low cardiac output. Identifying patients with truly low cardiac output in need of inotropic support can be challenging, while selecting the proper agent according to patients’ clinical profile and limiting infusion to the shortest time and lowest dose possible are important to optimize inotrope use. Levosimendan bears some advantages in this setting, especially for its beneficial effects in presence of beta-blockers, and its positive renal effects.

In AdHF, inotropic agents are required for the relief of persistent symptoms and the improvement of quality of life. Day clinic-based or home-based repetitive infusions may reduce hospital admission, which is a key factor in the quality of live and perhaps overall prognosis of the disease. Levosimendan bears an advantage in this setting due to its long-acting active metabolite.

The paper provides a practical approach to the three main steps required for the optimal use of inotropes in heart failure, namely (i) the identification of the right patient, (ii) the choice of the proper inotrope and (iii) the definition of the adequate weaning time.

The effects of inotropes on QoL in general, remain poorly defined, and more studies on this important and clinically meaningful aspect of AHF and AdHF patient care are warranted.

4 October 2019

October 2019 post

At the European Society of Cardiology Congress in Paris, the results of the GALACTIC trial were reported by Prof. Müller (Basel). Early intensive vasodilation using personalized high doses of nitrates, oral hydralazine and rapid up-titration of ACE inhibitors or angiotensin II receptor blockers did not improve 180-day mortality in a cohort of 781 acute heart failure patients. This trial is notable, among other things, for the fact that short-term use of conventional “tried and tested” (and extremely cheap) vasodilators, administered in an intensive regime and at high dose was just as ineffectual at influencing longer-term mortality as novel agents such as ularitide and serelaxin.

The inability to demonstrate survival benefit even from drugs that are established as part of the therapeutic armamentarium for AHF highlights some fundamental issues contributing to the paucity of new drug therapies in recent decades: for example, are we targeting the wrong pathological processes in our drug development programmes or are we privileging inappropriate endpoints in clinical trials and thus hampering the regulatory approval of useful new agents?

The general lack of evidence for an ongoing survival benefit from acute-phase treatments for AHF requires some reflection. While perhaps not fully subscribing to its philosophical outlook we find much to agree with in the views of McCullough [McCullough, P.A. How Trialists and Pharmaceutical Sponsors Have Failed Us by Thinking That Acute Heart Failure Is a 48-Hour Illness. Am J Cardiol 2017, 120, 505–508.], who has argued that AHF (and by extension AdHF) is a situation often long in the making and that to expect any therapy administered for <48 h to make a robust difference to survival or rehospitalization many months after the index admission is to misunderstand the pathophysiology of these conditions.

Hospitalization for heart failure, whether as a presentation of AHF or a decompensation in the context of AdHF, results in a down-shift in the trajectory of the syndrome that is associated with worsening outcomes and patient quality of life and increased costs of care. Medical progress to address these challenges has substantially stalled in the past 20 years but advances in data technology and analytics, along with developments in clinical trials design now offer opportunities to re-envision heart failure as a complex pathophysiological continuum in ways that may help to bring a new generation of therapies into clinical use. Meanwhile it would be advisable for the clinicians to evaluate if the nearly total absence of evidence of benefit with some of the traditional i.v. drugs used in AHF and AdHF (such as the catecholamines) warrants their elimination from routine use in favor of treatments where such evidence has been accrued.

10 September 2019

September 2019 post

ESC Congress 2019 was an astonishing success: over 32000 visitors at a program spanning from Saturday Aug 31 to Wednesday Sept 4 and focused on the best and latest science with renowned leaders in cardiovascular medicine. Being the largest such gathering in the world, ESC displayed more than 500 sessions during the five-day conference.

It is one of the professional events I cannot afford to miss: it is exciting to be part of a congress that covers so many interesting topics in cardiology. Everything is here together – science, practice, exhibitions, interesting people. A unique opportunity to get connected with experts coming from all over the world and present original research. At ESC Congress, I had the opportunity to keep abreast of the latest news in cardiology and talk about the results of my own research to colleagues from many other countries: ESC Congress did definitely provide a stimulus for my further research and practical work in my practice.

Now – after such a great moment - I strongly suggest everyone to review the ESC365 Congress resources: slides, videos and abstracts from ESC 2019.

Among the highlights, a satellite symposium was held in “The HUB Duras” on Monday Sept 2 from 13:00 to 13:45 on “Inodilators in Acute and Advanced Heart Failure” (John T PARISSIS (Athens, Greece) and Francesco FEDELE (Roma, Italy), as chairs, while the lectures and discussions were held by Finn GUSTAFSSON (Copenhagen, Denmark), Veli-Pekka HARJOLA (Helsinki, Finland), yours truly Gerhard PÖLZL (Innsbruck, Austria), Josep COMIN-COLET (Hospitalet De Llobregat, Spain), Piergiuseppe AGOSTONI (Milan, Italy), and Carsten TSCHOEPE (Berlin, Germany).

As it regards the LEODOR study (“repetitive use of levosimendan in advanced heart failure patients”), an investigator meeting was held to discuss about the progress in initiation of the centers and enrollment of the patients.

1 August 2019

August 2019 post

The countdown to ESC Congress 2019 is nearing its end. The world's premier Cardiovascular congress is now just less than 4 weeks away! The program spans from Saturday Aug 31 to Wednesday Sept 4.

Among the late-breaking science session, Prof. Müller will present the data of the GALACTIC trial (“Goal-directed AfterLoad Reduction in Acute Congestive Cardiac Decompensation: a randomized controlled trial”) at 11:36 on Monday in the main auditorium.

Also the main results of THEMIS (“Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study”) and ISAR-REACT 5 (“Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome”) will be presented and discussed.

The ESC TV services will broadcast throughout the congress. As an example, the PARAGON-HF (“Angiotensin Receptor Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction”) t will be discussed on TV by Scott Solomon on Sunday at 16:25. Stay tuned in the right channel.

To be mentioned also that the data of AFIRE (“Rivaroxaban monotherapy versus combination therapy in patients with atrial fibrillation and stable coronary artery disease”) will be disclosed.

As it regards the LEODOR study (“repetitive use of levosimendan in advanced heart failure patients”), an investigator meeting will be held to discuss about the progress in initiation of the centers and enrollment of the patients. The study protocol will be discussed in a satellite symposium in “The HUB Duras” on Monday Sept 2  from 13:00 to 13:45

The chairpersons of the symposium will be John T PARISSIS (Athens, Greece) and Francesco FEDELE (Roma, Italy), while the lectures and discussions will be held by Finn GUSTAFSSON (Copenhagen, Denmark), Veli-Pekka HARJOLA (Helsinki, Finland), yours truly Gerhard POLZL (Innsbruck, Austria), Josep COMIN-COLET (Hospitalet De Llobregat, Spain), Piergiuseppe AGOSTONI (Milan, Italy), and Carsten TSCHOEPE (Berlin, Germany).

The use of inotropes for correcting hemodynamic dysfunction and relieving symptoms in patients with congestive heart failure will be debated. Unfortunately, negative or insufficient data has been collected on the effects of cardiac glycosides, cathecolamines and phosphodiesthrase inhibitors on quality of life and survival. However, drugs which are both calcium sensitizers and potassium channels openers – such as levosimendan - have been proposed as safer inodilators in acute and advanced heart failure.  

3 June 2019

June 2019 post

Back from the HEART FAILURE congress in Athens with pleasant memories, new acquaintances, and a big bag with information and ideas.

LEODOR study on “repetitive use of levosimendan in advanced heart failure patients” has been discussed in the main program (see presentation in MyESC) and an investigator meeting has been held to discuss about the progress in initiation of the centers and enrollment of the patients.

As it regards the inodilator levosimendan, many posters were presented and a series of tutorials on i.v. vasoactive drugs in the treatment of acute and advanced heart failure was held by 12 speakers from Austria, Cyprus, Finland, Germany, Greece, Hungary, Italy, Spain, Sweden, and Switzerland. The lectures were recorded and the videos are available on the landing page www.acutehf.com/hf for educational purposes.

The speakers agreed that, despite the use of i.v. vasoactive drugs, diuretics, vasodilators and inotropes, for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades, insufficient data has been collected on their effects on Quality of life (QoL) and long term survival. Of particular note is that for inotropes belonging to the cardiac glycoside, catecholamine, and phosphodiesterase inhibitor families, data on the impact of these agents on QoL and survival are not positive and in several cases indicate an increase in mortality risk.

In acute heart failure, selecting the proper agent according to patients’ clinical profile and limiting usage to the shortest time at the lowest effective dose are important considerations to optimize inotrope use. In these settings, levosimendan bears an advantage also due to its beneficial renal effects. Levosimendan’s overall hemodynamic profile and clinical tolerability, combined with its extended duration of effect, has encouraged its intermittent use also in patients with advanced heart failure, to promote functional independence and quality of life and avert the need for unplanned hospitalizations resulting from episodes of decompensation. Further clinical research is in progress to refine the drug’s use for this purpose.




14 May 2019

May 2019 post

The HEART FAILURE meeting in Athens is approaching. On the web pages of the ESC it is already possible to have a glance over the final program of the congress.

Organised by the Heart Failure Association of the European Society of Cardiology, the Heart Failure Congress is a unique forum where cardiologists, interventional heart failure  specialists, cardiac surgeons, internists, practicing general physicians, basic scientists,  epidemiologists, cardiac nurses, industry affiliates and others have the opportunity to meet and exchange ideas and information.

The HFA congress is an international event open to healthcare professionals interested in any aspect of heart failure from epidemiology, through basic and translational science to prevention (reviewing the treatment of hypertension and post-infarction care), diagnosis (including novel imaging modalities and biomarkers), monitoring (together with remote monitoring), prognostication (risk stratification as well as use of biomarkers), medical and nursing management (including drugs, devices, tele-care and surgery).

I will be there presenting a rapid fire abstract on “repetitive levosimendan infusion” on Monday at 09:40 on the AGORA 2 stage: see you there!

Included in the program, some tutorials on how to use medications and devices are also accessible to the participants. As an example Orion Pharma will organize a series of 12 lectures on the use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure. Over many decades, negative or insufficient data has been collected on the effects of cardiac glycosides, cathecolamines, and phosphodiesthrase inhibitors on quality of life and survival. More recently, the calcium sensitizer and potassium channel opener levosimendan have been proposed as a safer inodilator. The tutorials lectures in Athens will focus on how to use safely and effectively levosimendan in acute and advanced heart failure.

2 April 2019

April 2019 post

Among the recent literature on Advanced Heart Failure which I found on PubMed, I particularly enjoyed reading the opinion paper by Burnside et al on the American Journal of Hospital Palliative Care (2019, ePub Mar 28, doi: 10.1177/1049909119838250).

The authors state that "Advanced heart failure therapies such as ventricular assist devices and home inotrope use are becoming more common. Technology advances as well as increased indications for use of such therapies is leading to a higher percentage of patients with end-stage heart failure receiving these therapies at end of life.".

In the manuscript, the authors present a case of a young man with dilated cardiomyopathy who undergoes advanced cardiac care in the setting of progressively declining cardiac function, which outlines the importance of acute care, palliative care, and hospice services being coordinated prior to and during acute-care services to provide goal-concordant and expeditious care. With advancing medical therapies for heart disease, increased coordination and collaboration of services are needed, particularly between hospice and acute-care services.

I would like also to mention the work by Shoaib et al (Int J Cardiol. 2019. ePub on Mar 15, doi: 10.1016/j.ijcard.2019.03.020) which describe the “Characteristics and outcome of acute heart failure patients according to the severity of peripheral oedema”.

The authors state that "Most trials of patients hospitalized for heart failure focus on breathlessness, but worsening peripheral oedema is also an important presentation." They investigate the relationship between the severity of peripheral oedema on admission and outcome amongst patients with a primary discharge death or diagnosis of heart failure. Of 121,214 patients taken into consideration in their research, peripheral oedema on admission was absent in 24%, mild in 24%, moderate in 33% and severe in 18%. Median length of stay was, respectively, 6, 7, 9 and 12 days (P- < 0.001), index admission mortality was 7%, 8%, 10% and 16% (P- < 0.001) and mortality at a median follow-up of 344 (IQR 94-766) days was 39%, 46%, 52% and 59%. In an adjusted multi-variable Cox model, length of hospital stay and mortality during index admission and after discharge increased progressively with increasing severity of peripheral oedema at admission.

Finally, I considered it worth of reading the small retrospective study of six patients by De Lazzari et al (Comput Methods Programs Biomed. 2019;172:117-126) who focused on how LVAD support influence ventricular energetics parameters in advanced heart failure. The analysis of ventricular energetics parameters based on external work and pressure volume area confirmed LVAD support as a beneficial therapeutic option for the patients considered eligible for this type of treatment. The authors conclude that a quantitative approach with the ability to predict outcome during patient's assessment may well be an aid and not a substitute for clinical decision-making. 



5 March 2019

March 2019 post

It’s a year since I reported on the status of the LeoDOR study (Repetitive Levosimendan Infusion for Patients With Advanced Chronic Heart Failure) so I think it’s more than time to bring readers up to date with our progress.

Since I last wrote on this subject the protocol for the study, authored by myself and 13 distinguished colleagues, has been published [Pölzl G et al. ESC Heart Failure 2019;6(1):174-181 DOI:10.1002/ehf2.12366].

The trial’s dedicated website, https://leodortrial.com/, is up and running and offers information to prospective patients and investigators, including a Trial Information Sheet and Site Evaluation documents for the latter and clear plain language answers to questions such as “What is the purpose of this study” and “What does taking part in this study involve?” for the former. LEODOR researchers can keep up-to-date and exchange thoughts and information via the sharepoint facility operated via the website.

The first 10% of the planned 264 patients have been enrolled, and the dedicated Twitter feed (@LeodorTrial) has announced the participation of several centres in Germany, including Innsbruck (where the first patient was recruited), Linz, Berlin, Braunau, Kiel, Würzburg, plus Oulu (Finland), Debrecen (Hungary) and Ljubljana (Slovenia).

Underpinning and inspiring all these exertions is the fact that while findings from over 10 double-blind clinical trials or registries (including LevoRep, LION-HEART, LAICA, RELEVANT, etc.) have consistently supported the view that repeated infusion of levosimendan benefit patients with advanced heart failure, no single study has been statistically powered enough to generate conclusive results. Clearly, a larger study is needed and it is our confident hope that LeoDOR (NCT03437226) will be that trial.

LeoDOR is the first major trial of intermittent levosimendan to use a global rank score methodology to assess the impact of therapy. This global rank endpoint is a composite of: (i) time to death or urgent heart transplantation or VAD implantation: (ii) time to a non-fatal HF event requiring i.v. vasoactive therapy, and: (iii) time-averaged proportional change in NT-proBNP from baseline to 14 weeks. This novel methodology allows each patient to contribute to the overall endpoint, thereby optimizing statistical power while keeping the number of patients within manageable limits.

We’re a way off seeing the final results of LeoDOR yet and I expect to deliver more updates via this blog before that day arrives, but the study is now well and truly underway: I extend my best wishes and gratitude to all patients and investigators who have agreed to contribute to this important initiative in advanced heart failure treatment.




7 February 2019

February 2019 post

Maximizing benefits of levosimendan for patients for 30 years  - and the work continues..

If newspapers are the first draft of history for the lay public, posters and abstracts serve the same role for scientists and clinicians. We might therefore conclude that levosimendan has been making history for 30 years, since it first appeared in congress posters and abstracts in the late eighties. The volume of research material generated during those years has been quite remarkable, with many hundreds of reports being published since the start of the present century. Abstracts on levosimendan can be found at key annual congresses of scientific and clinical societies such as the ESC, the HFA, the ISICEM, the ESICM, the EACTA, the EACTS and more.

Communications at congresses on levosimendan span between preclinical pharmacology and a series of clinical investigative phases, some of which remain as interesting observations, others of which ripen into new or enlarged clinical applications or offer a side-light on contemporary clinical practice (as in the 2011 report by Dr JT Parissis et al on ” Gender-related differences in clinical phenotype and in-hospital management in patients with acute heart failure: an ALARM-HF survey sub-analysis.").

All in all, Levosimendan continues to excite the imagination of scientists and researchers in all those directions.

In the sphere of clinical development, recent years have witnessed a concentrated emphasis on exploiting the unique qualities of levosimendan to maximize benefit to patients with acute or advanced heart failure. Contributions in this area have included a large, important and still growing literature describing first-hand experience with levosimendan in the day-to-day management of these cases. As part of these investigations we have also seen in very recent years expansion of research into matters such as the impact of levosimendan on renal function in heart failure, the use of intermittent levosimendan as a bridge to heart transplant and the use of this drug in the context of ECMO treatment.

Another step in the evolution of this remarkable and versatile agent is now in progress with the recent presentation by Dr Merit Cudkowicz et al. of the protocol of the REFALS 3 trial, which will evaluate the impact of levosimendan on respiratory function in patients with acute lateral sclerosis (ALS). Details of this ambitious trial are available via www.ClinicalTrails.gov (ClinicalTrials.gov Identifier: NCT03505021).



10 January 2019

January 2019 post

Supplement to the European Heart Journal

The new year is up and running and I take this opportunity to wish all visitors and subscribers to www.simdax.com good health and fulfillment in 2019.

My first blog post of the year is an invitation to you all to take a look at a supplement to the European Heart Journal that hit the bookshelves right at the end of 2018. I must declare an interest in the matter as I was the Supplement Editor but, even allowing for the natural pride in ownership that position evokes, I think this is a commendable addition to the literature on acute and advanced heart failure and will reward readers’ attention.

The bone and muscle of the essays this Supplement was provided by my 16 distinguished fellow physicians from across Europe. Space prevents me name-checking them all here and to be selective would intolerable but their credentials as commentators on these matters are undisputed and their thoughts on these subjects merit our attention.

I’m going to pick out two thoughts of my own, from my Editorial, to try and convey the enquiring tone of these essays and to encourage you to give the full Supplement some of your time.

“Patients [with Advanced Heart Failure] are vulnerable to repeated cycles of decompensation and hospitalization. Such episodes are debilitating for the patient and expensive for the health system. If we can intervene to restore equilibrium to patients in the vital time between the start of a phase of deterioration and the eventual hospitalization we could contribute significantly to their health-related quality of life and spare them the disappointment of yet another unscheduled hospital admission.”

“There is certainly enough evidence to identify levosimendan as one valuable element in an overall strategy of care directed towards maintaining patients in a condition of out-of-hospital stability.”



Poelzl G. Levosimendan in acute and advanced heart failure: still some chapters to be written. I1: 20(Suppl I):2018.

Harjola V-P et al. Use of levosimendan in acute heart failure. European Heart Journal Supplements. I2-I10: 20(Suppl I):2018.

Oliva F et al. Repetitive levosimendan treatment in the management of advanced heart failure. I11-I20: 20(Suppl I):2018.

3 December 2018

December 2018 post

Levosimendan Ends 2018 on a High Note

Earlier this year (May 27-28), the Heart Failure 2018 congress of the European Society of Cardiology-Heart Failure Association convened in Vienna, Austria.  A series of tutorials delivered by experts from nine European countries examined how to use levosimendan safely and effectively in acute and advanced heart failure, including in the context of renal dysfunction.

Contributors to that lecture series have now distilled into print their experience and views on the position of levosimendan in the management of acute and advanced heart failure in a review published in Cardiovascular Drugs and Therapy (Bouchez S et al. 2018 Nov 6. doi: 10.1007/s10557-018-6838-2. [Epub ahead of print]). It seems fitting that we should conclude our monthly blog posts for 2018 with a brief summary of this excellent tour d’horizon from a group of notable and respected practitioners in this complex field.

A series of major points emerged from this review.

(1)  Meta-analyses of levosimendan data in various settings, including AHF and AdHF, indicated a trend towards a survival benefit that reached statistical significance in some investigations, though not all. Of note, however, none of these meta-analyses produced any indication that the use of levosimendan is associated with an increase of mortality, whereas a worsening impact on survival has been reported for other inotropes or inodilators.

(2)  In advanced heart failure meta-analysis indicates a clear and consistent effect of levosimendan to reduce re-hospitalizations. Given that patients with AdHF may comprise up to 10% of the overall heart failure population these benefits may be accessible to substantial numbers of patients.

(3)  Bouchez and colleagues re-iterate the advice of the authors of the 2016 ESC guidelines on acute and chronic heart failure, who recommend use of levosimendan in cases where there is concomitant use of beta-blockers.

(4)  Levosimendan both in the acute setting and in the repetitive/intermittent context of AdHF appears to a promising option to improve renal perfusion or to reverse or ameliorate renal dysfunction but further controlled trials are needed to confirm the status of levosimendan for this purpose. In particular, they emphasize the conclusions of Lannemyr et al. who recently suggested that levosimendan “could be the preferred inotropic agent for treatment of the cardiorenal syndrome”. (J Am Heart Assoc. 2018;7: e008455. doi: 10.1161/JAHA.117.008455.)

These are substantial attainments for any drug in these areas of heart failure therapy and they confirm levosimendan as a uniquely-configured resource for this field. Join us again in 2019 for the next chapters in the development of this remarkable agent.




7 November 2018

November 2018 post

The price of the drug is only part of the cost of treatment

Among cardiovascular diseases, heart failure (HF) is often referred to as a ‘final-stage’ condition. The prognosis is poor, with a mortality rate of approximately 50% within the first 5 years following diagnosis [Liao L et al. Economic burden of heart failure in the elderly. Pharmacoeconomics. 2008;26:447–62].

Patients with advanced HF (AdHF) are a relatively small but important contingent of the wider HF population who face substantial morbidity through continued deterioration of symptoms, and frequent hospitalization. AdHF places a considerable economic burden on hospital budgets, and therapies aimed at reducing the re-hospitalization rate have the potential to be of great economic value.

A useful contribution on this theme appeared earlier this year in the form of an abstract presented at the 2018 World Congress on Acute Heart Failure [Eur J Heart Fail. 2018;20 (Suppl. S1):398]. Prepared by Dr Josep Comin-Colet of the Bellvitge Hospital, Barcelona, Spain and fellow LION-HEART investigators, plus Spanish experts in health economics and outcomes research, this work reported on the net cost of intermittent intravenous levosimendan, given as an outpatient treatment to patients with AdHF.

Levosimendan therapy in the LION-HEART RCT reduced the rate of hospitalization for HF from the 66.7% seen in the control group to 22.9%. Hospitalizations for worsening HF are expensive: averting them saves money as well as improving patients’ quality of life. In the case of the Spanish centres enrolled in LION-HEART, the per-patient saving realized by using intermittent levosimendan was €2978.16. By including costs of the medications and other costs, therefore, use of intermittent levosimendan saved over €1000 per patient, net.  A probabilistic analysis suggested a 94% chance of a saving.

The lesson from this research—and it’s not the first time such a lesson has emerged from pharmaco-economic analyses of levosimendan—is that the price of the drug is only part of the cost of treatment and that interventions that avert HF-related hospitalizations can in fact be much more affordable than a narrow focus on the unit price might suggest. Such outcomes are also of significant benefit to many patients and we should never lose sight of that.

19 October 2018

October 2018 post

Greetings from expert meeting in Athens

An expert meeting organized by the Heart Failure Clinic, Attikon University Hospital, was held in Athens on Sept 27-28 on the theme “Inotropes for the management of acute and advanced heart failure: practical considerations, tips and tricks, future directions”.

Thirty-five experts from 21 European countries ranging geographically from Finland and Russia via Turkey and Israel to Cyprus and Spain grappled with the live issues of the field, including the definitions of acute and advanced heart failure, the need for haemodynamic, neurohormonal and symptom stabilization, the ambition for (and sometimes tension between) quality and quantity of life, the uses of inotropes and their effects on the heart, lungs, kidney, and other organs in those settings. A consensus publication on the practical use of inotropes in those settings is planned for Q1 2019, with special focus on levosimendan.

This meeting represents the continuation of an initiative developed during the past decade and intended to promote clinical awareness of levosimendan while ensuring that the science and clinical experience underpinning the drug’s status in the cardiology repertoire is subject to regular updating and rigorous scrutiny through consensus development and peer review [1-7]. Having participated in several of these meetings I can attest to the calibre of the faculties involved, the depth and breadth of the discussions and the even-handed way that data is analysed and conclusions are reached. These meetings are not just a chance to catch up with colleagues in an agreeable location: there is a commitment to reaching and publishing serious reflections on best practice. Here are some examples from previous meetings held under the same auspices, all of which reward the effort of reading.

  1. Nieminen MS et al. The role of levosimendan in acute heart failure complicating acute coronary syndrome: A review and expert consensus opinion. Int J Cardiol. 2016;218:150-157.
  2. Nieminen MS et al. The patient perspective: Quality of life in advanced heart failure with frequent hospitalisations. Int J Cardiol. 2015;191:256-64
  3. Nieminen MS et al. Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus. Int J Cardiol. 2014;174(2):360-7.
  4. Yilmaz MB et al. Renal effects of levosimendan: a consensus report. Cardiovasc Drugs Ther. 2013;27(6):581-90.
  5. Pölzl G et al. Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy. Int J Cardiol. 2012;159:82-7.
  6. Farmakis D et al. Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper. Int J Cardiol. 2016;222:303-312
  7. Altenberger J et al. Levosimendan in Acute and Advanced Heart Failure: An Appraisal of the Clinical Database and Evaluation of Its Therapeutic Applications. J Cardiovasc Pharmacol. 2018;71(3):129-136

17 September 2018

September 2018 post

The 2018 congress of the European Society of Cardiology (ESC), recently concluded, has re-affirmed the exceptional status of this globe-spanning scientific endeavour. Society sources report that over five days, delegates from more than 150 countries presented, discussed or attended 4,500 abstracts in 500 expert sessions covering 400 cardiology topics. A total of 92 late breaking science studies were presented including 17 Late Breaking Clinical Trials, six Clinical Trial Updates, and 20 Registries: these are extraordinary numbers.

Exceptional also is the calibre of the materials now being brought into the public domain. In the arena of acute heart failure the VERDICT trial produced the perhaps surprising but undoubtedly important finding that very early diagnosis and treatment in patients with non-ST segment elevation acute coronary syndrome was not superior to a strategy of assessment deferral: postponing invasive examination and treatment for up to 72 hours appears to be successful as a very early approach.

In parallel with these mainstream activities, the practical tutorials lectures that I trailed in my August post were a great success, with high rates of attendance. In three full days, a faculty of 17 acknowledged experts dealt purposefully and informatively with major themes relating to the use of inodilators, particularly levosimendan, in acute and advanced heart failure. All the presentations, including the Q&A sessions which followed all lectures, were recorded and may be viewed freely at www.acuteHF.com.



3 August 2018

August 2018 post

The summer holiday season is in full swing and I hope yours is going well.

Science and medicine never entirely stop, however, and many of us will spend at least a little time in the coming weeks devising our schedules for the 2018 congress of the European Society of Cardiology, which convenes this year in Munich, Germany from Saturday 25 August to Wednesday 29 August.

In amongst the main schedule of the congress is a series of very attractive symposia supported by Orion Pharma that I take this opportunity to draw to your attention.

You can get full particulars of the programme here. The aspects that draw my particular attention are:

(1) this is a lecture series with an unashamedly practical emphasis that addresses the major questions in the management of patients with acute or advanced heart failure

(2) this advice is offered by a faculty every member of which is an acknowledged and respected practitioner in this area of cardiology whose experience in these often difficult cases has been acquired at the bedside and at first-hand. They know what they are talking about.

So, if you are planning to attend ESC 2018 block out some time in your congress programme book or your congress programme app and come to some of these tutorials: they’re concise, they’re lively and they’re packed with information. The whole programme repeats from Sunday to Tuesday, so there’s ample opportunity for you to fit in the whole series, plus there’s a promise of light refreshments that may be especially welcome if Europe’s summer heat-wave lasts to the end of August!

7 June 2018

June 2018 post

Another Uptick for Levosimendan in Advanced Heart Failure

When the Heart Failure Association of the European Society of Cardiology (HFA-ESC) issues a fresh position paper on the identification and management of advanced heart failure this blog has a duty to pay attention. Well, the HFA-ESC has issued a fresh position paper [Crespo-Leiro MG et al. Eur J Heart Fail. 2018 May 27. doi: 10.1002/ejhf.1236] and here’s our first take on some highlights.

(1) A new definition of advanced heart failure

The Association offers a new definition that reflects the altered medical and scientific landscape of the past decade. Technically, this new definition rests on 4 clinical criteriaall of which must be present despite optimal guideline-directed treatment but its philosophy is found in the advice that “[Diagnosis of] advanced heart failure does not depend on ejection fraction, but on the patient’s symptoms, prognostic markers, presence of end-organ damage, and goals for therapy.”

It’s worth also noting that the HFA-ESC regards unplanned outpatient visits for worsening symptoms of heart failure as a significant sign and gives such visits the same diagnostic value as a heart failure-related hospitalization. This is consistent with its stance that advancing heart failure represents “a decompensated and unstable state in which standard treatment is, by definition, insufficient”.

(2) Recognition for levosimendan

Levosimendan emerges quite strongly from the new HFA-ESC position paper: it’s worth quoting verbatim some key statements:

(1) Intermittent use of inodilators for long-term symptomatic improvement or palliation has gained popularity, especially use of levosimendan, since the hemodynamic effects may last for >7 days after a 12–24 h infusion because of the pharmacologically active metabolite with a long half-life.

(2) Meta-analyses of several heterogeneous small trials of a [levosimendan] repeated infusion strategy have suggested a positive effect on survival and a reduction in hospitalizations.

(3) In the LION-HEART pilot study patients randomized to levosimendan were…less likely to be hospitalized for heart failure or experience a decline in health-related quality of life compared to placebo. Adverse events were similar between groups.

Medication can only be short-term response to the challenge of advanced heart failure but these notes from the HFA-ESC indicate that within that remit levosimendan is moving into the mainstream and may be considered as a bridge strategy to sustain a patient until mechanical circulatory support or a heart transplant can be provided.

8 May 2018

May 2018 post

Levosimendan in Cardiac Surgery: The Evidence Adds Up


If we had a way to reduce the risk of life-threatening complications after cardiac surgery would we use it?  Of course we would. It is for reason that this month’s blog post highlights the recent work of Dr. Qiang and colleagues [1]. In the most up-to-date and comprehensive research of its kind these researchers identified and analyzed data from 25 randomized controlled trials (RCTs) that compared perioperative use of levosimendan with control (placebo, conventional inotropes or intra-aortic balloon pump) in 3247 adult cardiac surgery patients and reported an impressive array of benefits. The main results are that


1. Levosimendan reduced mortality after cardiac surgery (OR 0.63; P=0.001). This survival benefit was not confined to patients with markedly reduced left ventricular ejection fraction (LVRF): it extended to patients with LVEF up to 50%. So even patients with only moderate depression of LVEF gained from levosimendan treatment.


2. Levosimendan use also significantly reduced: the incidence of postoperative acute kidney injury (OR 0.55; P<0.0001), the use of renal replacement therapy use (OR 0.56; P=0.002), the duration of ICU stay (weighted mean difference [WMD] -0.49 day; P=0.0002), and the duration of mechanical ventilation (WMD -2.30 h; P=0.002).


Data of this sort make a strong case for the peri-operative use of levosimendan in adult cardiac surgery but they can’t answer every question. In particular, the outcomes of some recent randomized trials [2,3,4] points to the need for further work to define the optimal dose-range: Qiang and colleagues [1] suggest that adult cardiac surgery may be a situation where initial bolus dosing and a relatively high infusion rate may be needed to secure the full clinical benefit of levosimendan unique inodilator actions. If that proves indeed to be the case then the well-documented safety profile of levosimendan will by another feature favoring its use.



1. Qiang H et al. J Cardiovasc Pharmacol 2018 Publish Ahead of Print Apr 3. PMID: 29672418, DOI: 10.1097/FJC.0000000000000584
2. Landoni G et al. N Engl J Med. 2017;376(21):2021-2031
3. Mahta RH et al. N Engl J Med. 2017;376(21):2032-2042
4. Cholley B et al. JAMA. 2017;318(6):548-556

5 April 2018

April 2018 post

What does the Advanced Heart Failure patient want?

In the preamble to their recent paper “Development and testing of a goals of care intervention in advanced heart failure” [Appl Nurs Res. 2017;38:99-106] Professor Cynthia M Dougherty and colleagues outline an array of options for the treatment of advanced heart failure (HF) that create – quite reasonably – the impression that we are in a golden age of therapeutic possibilities for this difficult condition: recurrent parenteral infusions, implanted ventricular assist devices and cardioverter defibrillators, cardiac transplantation, and the total artificial heart.


But is a life dominated by this panoply of interventions in every case what our patients want? Maybe; maybe not: and very likely not the same answer every time. We have a responsibility to identify their goals.


Dougherty and colleagues’ article is a contribution to the expanding science of “goals of care (GoC)”. I am not going to do them the discourtesy of trying to summarize a complex and supple piece of research in this short blog beyond revealing that giving patients’ the skills and confidence to initiate and maintain constructive conversations about what they want from their treatment emerges as a vital aspect of excellence in medical care for advanced heart failure.


In the authors’ own words “Holding a GoC conversation between patient and provider is expected to facilitate concordance between care received and the patient’s values and goals, assist in shared decision making about possible new HF therapies, improve patient-provider communication, and potentially improve quality of life.” We have to note that “is expected”: the outcome we aspire to may not be fully achieved in every case. But to aspire to those outcomes is from every point of view absolutely the right thing to do and I would urge all those involved in the care of patients with advanced heart failure to make a careful study of research on GoC (below are some other recent leads to get you started) and to bring well-founded understanding of patient goals and wishes into the heart of their practice.



• An Intervention to Enhance Goals-of-Care Communication Between Heart Failure Patients and Heart Failure Providers.[J Pain Symptom Manage. 2016]

• Does an intervention designed to improve self-management, social support and awareness of palliative-care address needs of persons with heart failure, family caregivers and clinicians?[J Clin Nurs. 2018]

• Feasibility and acceptability of a nursing intervention with family caregiver on self-care among heart failure patients: a randomized pilot trial.[Pilot Feasibility Stud. 2016]

14 March 2018

March 2018 post

I am pleased to announce that there have been notable advances in the LEODOR trial (Repetitive Levosimendan infusions for patients with advanced chronic heart failure), a randomized, double-blind, placebo-controlled multicenter study sponsored by the University of Innsbruck and supported by a grant of Orion Pharma.


The recent achievements include:

- Recruitment of the first patient of a planned 276 cases hospitalized for decompensated heart failure requiring i.v. diuretics, or i.v. vasodilators, or i.v. inotropic therapy, or some combination of these interventions.
- Submission of a formal synopsis of the study protocol to Eur. J. Heart Failure for peer review and publication.


On the administration and communication side, LEODOR is now represented on the internet by its own website (http://leodortrial.com/) which proves a wealth of information for everyone with an interest in the conduct and progress of the study and regular updates on recruitment. The “For Patients” page addresses key questions such as:

- What is the purpose of this study?
- Which patients will be chosen to take part?
- What does taking part in this study involve?

While the “For Investigators” page summarizes the aims, design and eligibility criteria for LEODOR and provides additional technical and professional information on subjects including Trial Synopsis, Site Evaluation and Patient Consent through a suite of downloadable PDFs (via http://leodortrial.com/#investigators). The site also offers visitors a photo galley of the 14 principal investigators and a range of opportunities to contact the LEODOR team, which in the fullness of time will include tweets posting significant milestones in the progress of the trial. Go Team LEODOR!

12 February 2018

February 2018 post

Levosimendan roars ahead as LION-HEART results published

Important new support for the use of levosimendan in the management of advanced heart failure (AdHF) has emerged from the LION-HEART study, primary results of which have recently been published in the European Journal of Heart Failure (10.1002/ejhf.1145).

The unique pharmacodynamic and pharmacokinetic qualities of levosimendan have already made it a drug of interest for treating AdHF through intermittent i.v. infusions. LION-HEART is one of the multicenter, double-blind, randomized, parallel-group, placebo-controlled trials in this area of medicine.

The 69 patients in LION-HEART were recruited at 12 centers in Spain: they had chronic AdHF (NYHA grade III or IV) and low mean ejection fraction (~26%). They were randomized in a 1:2 ratio to placebo or to levosimendan (0.2 mcg/kg/min, with no loading dose) administered for 6h in each of 6 treatment cycles at 2 week intervals.

Potent effects of levosimendan were observed on the study primary endpoint of serum concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 6-month follow-up. The proportion of patients exhibiting a reduction in NT-proBNP levels >25% from baseline was higher in the levosimendan group (48% vs. 9%; P=0.002) and the difference in average percentage change from baseline in NT-pro BNP strongly favored levosimendan (-20% vs. +50%; P<0.001).

Among secondary endpoints, patients treated with levosimendan experienced a reduction in the rate of HF-related hospitalization compared with placebo (hazard ratio 0.25; 95% CI 0.11–0.56; P =0.001) and were less to experience a clinically significant decline in HF-related quality of life in follow-up to 25 weeks (P =0.022).

18 January 2018

January 2018 post

News from the development front: Tenax Therapeutics backs Levosimendan for pulmonary hypertension

Levosimendan has received a big vote of confidence at the beginning of 2018 with the announcement of Tenax Therapeutics that it will conduct a Phase II of the calcium-sensitizing drug to manage Pulmonary Hypertension associated with Heart Failure and preserved Ejection Fraction (PH-HFpEF). As part of its development program Tenax Therapeutics has announced plans for to start its trial in PH-HFpEF in 3Q2018.

Why this move does make a lot of sense?


- Large unmet need: no drugs are approved for the treatment of PH-HFpEF, even though it is estimated to affect more than 1.5 million people only in the USA.

- Positive levosimendan data: preliminary studies are supportive of favorable effects of levosimendan in patients with pulmonary hypertension [Qiu J et al. Life Sci. 2017;184:30-36, Kleber FX et al. J Clin Pharmacol. 2009;49(1):109-15 ].

- Potential for flexible chronic therapy: thepharmacokinetics and long-lasting effects of levosimendan and its metabolite OR-1896 create potential to use chronic intermittent therapy in the treatment of PH-HFpEF.


Clinical experts who advised Tenax Therapeutics identified the novel mechanisms of action of levosimendan, initial experience with the drug in pulmonary hypertension, and its established position in the management of left and right ventricular failure, as providing a strong rationale for assessing it in PH-HFpEF.

5 December 2017

December 2017 post

Hospitalisation for the management of acute decompensation is a critical moment in the trajectory of heart failure (HF) and one that has gloomy prognostic implications for many patients. Outcomes for patients hospitalized with acute HF are poor, with high mortality and recurrent hospitalizations. The majority of those re-hospitalisations occur early after first hospital discharge: about a quarter of acute HF patients are re-hospitalised within the first month, and two-thirds within 1 year.

We have disappointingly few good options to offer patients during this period of vulnerability. Intermittent or continuous conventional inotropic therapy has been tested but, despite favourable indications from pilot trials, no positive effect on hospitalisations has been observed and possibly no benefit on mortality either.

Several clinical studies of the repetitive use of i.v. levosimendan have suggested that such a strategy may benefit patients with advanced HF, which was confirmed by the recent meta-analyses by Silvetti et al. A larger study, however, is needed to verify these favourable preliminary results and to explore the efficacy and safety of intermittent levosimendan therapy during the period of high vulnerability that follows a hospitalisation for acute HF.

The LeoDOR study has been designed to address this need. As a multicentre, randomised, double-blind, placebo-controlled, three-arm trial LeoDOR will explore the efficacy and safety of intermittent levosimendan therapy, given for 12 weeks either as a 6-h continuous infusion at a rate of 0.2 μg/kg/min every 2 weeks or as a 24-h continuous infusion at a rate of 0.1 μg/kg/min every 3 weeks.

Efficacy assessment in LeoDOR is based on a novel and ambitious composite outcome. in which all participants are ranked across three hierarchical groups in order of importance: top of that ranking comes (i) time to death or urgent heart transplantation or implantation of a ventricular assist device (VAD), followed by (ii) time to non-fatal HF requiring i.v. vasoactive therapy; and (iii) time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP). This imaginative outcome measure assigns proper weight to different outcomes and also enables every patient to contribute to the endpoint.  

The first patients will be enrolled in LeoDOR this month, December 2017 and will continue until Q2 2019, when it is planned to have enrolled 264 patients at 28 centres in nine European countries.  The LeoDOR study may bring some much-needed good news for a growing population of acutely ill HF patients and those responsible for their care.

1 November 2017

November 2017 post

Acute heart failure and renal function: an organ interplay not to be underestimated.

In “Cardiorenal Syndrome” by Ronco et al. (JACC 2008;52:1527-39) the authors identified 5 subtypes of cardio-renal syndrome (CRS) with distinctive pathophysiologies and described the nature of the co-dependencies of cardiac and renal dysfunction.


This mattered in 2008 and it matters today because, as Ronco and colleagues noted in their preamble, “A diseased heart has numerous negative effects on kidney function but, at the same time, renal insufficiency can significantly impair cardiac function.”


It matters also because of the numbers of patients affected and the consequences of CRS for patients with acute heart failure. Researchers in the Atherosclerosis Risk in Communities (ARIC) Study Community Surveillance programme have reported that “Severely reduced eGFR (<30 ml/min/1.73m2) was observed in ~30% of acute decompensated heart failure cases”.1 Elsewhere it has been reported that type-1 CRS (kidney injury secondary to acute cardiogenic shock or acute decompensation of chronic heart failure) “accounted for more than half of all mortality”.2  Age or geographical location are no protection from these malign effects.3,4


Both in 2008 and again more recently,5 Dr Ronco and colleagues called attention to the possible conceptual differences between chronic kidney disease and worsening renal function in acute heart failure and suggested that these may represent “different pathophysiological mechanisms in the setting of acute heart failure”. Multiple pathways that might contribute to these differences have been proposed.5,6


All of this is a reminder that the interplay between the acutely compromised heart and the kidneys is complex, with huge scope for variations of relevant pathophysiology between cases. Identifying the optimal treatment for individual cases is a correspondingly complex and demanding task.


In the therapeutic palette, levosimendan seems a reasonable option, in cases where cardiac output is compromised.7 In a tutorial lecture at the recent ESICM-LIVES congress in Vienna, Prof. Sven-Erik Ricksten (Sahlgrenska University Hospital, Gothenburg, Sweden) showed a profound difference in the effects of levosimendan vs dobutamine on glomerular filtration (see HERE) which would justify the selection of levosimendan as inotrope of choice for treatment of heart failure with concomitant renal failure.



1. Matsushita K et al. PLoS One. 2017;12(8):e0181373.
2. Pimienta González R et al. PLoS One. 2016;11(12):e0167166.
3. Saiki H et al. Heart Vessels. 2016;31(8):1313-8.
4. Sliwa K et al. Eur Heart J. 2013;34(40):3151-9.
5. Palazzuoli A et al. Eur Heart J Acute Cardiovasc Care. 2016;5(8):534-548.
6. Obi Y et al. Cardiorenal Med 2016;6:83-98
7. Yilmaz MB et al. Cardiorenal Med 2016;6:83-98.

6 October 2017

October 2017 post

What could be worse than heart failure? Perhaps advanced heart failure. The ESC and other expert cardiology groups have produced precise technical definitions of “advanced heart failure” but for many patients affected those definitions perhaps miss the central experience: every aspect of life as you know it and cherish it starts to slide from your grasp as your heart falters repeatedly and each recovery leaves you weaker and less independent than before.

We are not entirely without options for these critically vulnerable patients. Ivabradine may benefit the patient with tachycardia; even digoxin may retain a role for rate regulation in atrial fibrillation and for symptom relief. For selected patients with a strong renal dimension to their situation rolofylline, empagliflozin, or serelaxin may bring benefit though full characterization those drugs and their target populations is desirable.

For acute exacerbations of heart failure we face an emerging alphabet soup of natriuretic peptides (ularitide, cenderitide), beta-arrestin-biased angiotensin II type 1 receptor ligands (TRV120027), nitroxyl donors (CXL-1020, CXL-1427), soluble guanylate cyclase modulators (cinaciguat, vericiguat) and short-acting calcium channel blockers (clevidipine), in addition to familiar names such as nicorandil.

Increasingly there is the option of a left ventricular assist device (LVAD), which in an era when demand consistently exceeds supply is becoming a destination therapy for many patients who might otherwise qualify for a heart transplant.

It remains the case, however, for many patients whose condition continues to deteriorate even though they have “maxed out” on diuretics, beta-blockers and treatments directed at the rennin-angiotensin-aldosterone axis (including perhaps the combined angiotensin receptor blocker and neprilysin inhibitor LCZ696) that inotrope therapy is a key resource in gaining time and preserving quality of life while decisions are taken about heart transplantation, mechanical support or perhaps palliative care.

Conventional inotropes such as dobutamine or milrinone may improve symptom control but appear to do so at the expense of worsened mortality. In this landscape levosimendan stands out as a therapy that preserves or enhances ventricular function in an energy-neutral way and does not make patients choose between more life or better life – they can have both.

11 September 2017

September 2017 post

ESC 2017 in Barcelona

The annual congress of the European Society of Cardiology (in Barcelona, from the 26th to the 30th of August) was a unique occasion for updating our knowledge on Acute and Advanced Heart Failure. At “Village 9” the sessions were focused on Heart Failure, with insights on Pathophysiology and mechanisms, Epidemiology, prognosis and outcome, ventricular function & hemodynamics, Drug treatment, etc. Also in some of the very popular “Hubs” the sessions were often touching intriguing themes such “Can we teach heart failure drugs new tricks?”. Several Pharmaceutical Industries had organized either satellite symposia or series tutorials to complement the general program, and the daily agendas of the attendees went easily overbooked. In the field of Advanced Heart Failure, a series of hands-on tutorials was organized by Orion Pharma on the use of inodilators. The three days program included lectures by 14 European speakers (from Spain, Italy, Germany, France, Greece, Austria, Finland, and Russia) on the use of inodilators for correcting hemodynamic dysfunction and ameliorating symptoms in patients with advanced heart failure. Their main conclusion was that the calcium sensitizer and potassium channel opener drug family can be considered as a safe solution to achieve inodilation. 

Also the poster session was rich and stimulating. To be noticed, the first report of the RELEVANT-HF clinical trial on repetitive levosimendan in advanced refractory heart failure was presented by the Italian group of Prof. Fabrizio Oliva.  They concluded that, in patients with ARHF, scheduled repeated LEVO infusions resulted in a decrease in hospital admissions for worsening HF, expressed as proportion of days spent in hospital in the 6 months after with respect to the 6 months before start of planned treatment.

Finally, the Investigator Meeting of the LEODOR study (Repetitive Levosimendan infusions for patients with advanced chronic heart failure) was also held in Barcelona in occasion of the ESC congress. The study just started and over 30 centers are currently enrolling.

3 August 2017

August 2017 post

LION-Heart and LAICA clinical trials: differences and similarities


Advanced heart failure (AdHF) is associated with high morbidity and mortality and imposes considerable burdens on the health systems of developed countries. The LION-HEART (www.clinicaltrials.gov NCT01536132) and LAICA (NCT00988806) trials are part of a suite of clinical studies of intermittent levosimendan therapy in this setting.


The LION-HEART trial evaluated the safety and efficacy of repetitive 6-h doses of levosimendan (0.2 micrograms/kg/min) every 2 weeks, as compared to placebo. The primary endpoint is the change in NT-proBNP levels between baseline 12 weeks later in a population of 69 adult patients with left ventricular ejection fraction <35%a and diagnostic criteria of advanced chronic heart failure.


The LAICA study assessed the effects of intermittent levosimendan 0.1 micrograms/kg/min every 30 days for a year) on combined overall mortality rate and hospital admission rate for acute cardiac decompensation or HF worsening in 213 adults with AdHF of any etiology, including at least one admission for acute decompensation within 6 months prior to randomization. Sub-studies were planned to examine effects on renal function and the cost-effectiveness of levosimendan.


Both these Phase 4 trials, conducted in Spain, are double-blind and placebo-controlled. LION-HEART has a smaller patient population but is powered for its primary focuses on NT-proBNP levels, which are indicative of heart failure status. The larger LAICA trial emphasizes widely-accepted and established clinical and health-related quality of life outcomes. The results were presented in Seville (ESC-HF 2015) and Florence (ESC-HF 2016), respectively, and provide insights into the usefulness, effectiveness and safety of intermittent levosimendan as an addition to the pharmacological repertoire for advanced heart failure.

22 June 2017

July 2017 post

Heart failure is the leading cause of adult hospitalization in the industrialized world and imposes a substantial burden on the public health. The later stages of heart failure are characterized by a steady decline in quality of life and frequent re-hospitalization for recurrent acutization of the symptoms.1 Most of the re-hospitalizations take place relatively soon after discharge from the index hospitalization. About one quarter of patients are re-hospitalized within one month, and more than 60% of these re-hospitalizations are seen within 15 days after discharge.2

Several clinical studies have been performed on the repetitive use of intravenous levosimendan in Advanced Heart Failure.3 Their results are suggesting that repeated infusions of levosimendan bring advantages to patients with advanced chronic heart failure, both as it regards mortality4 and re-hospitalization.5 However, few of these studies were properly powered. Therefore, a larger study is needed to verify the favorable results.

In the newly commenced LEODOR study (www.leodortrial.com) the efficacy and safety of intermittent levosimendan therapy started during the vulnerable phase after a recent hospitalization for heart failure is tested. The hypothesis is that, compared with placebo, repetitive administration of levosimendan in the post-acute heart failure syndrome discharge period, will be associated with greater clinical stability through 14 weeks as assessed by a composite clinical endpoint consisting of mortality, acute heart failure episodes, and change in natriuretic peptide levels.

References: 1. Fruhwald S et al. Expert Rev Cardiovasc Ther. 2016;14:1335-1347. 2. Dharmarajan K et al. BMJ. 2013;347:f6571. 3. Pölzl G et al. Int J Cardiol 2017 [ePub May 23] doi: 10.1016/j.ijcard.2017.05.081. 4. Silvetti S & Nieminen MS. Int J Cardiol. 2016;202:138-43. 5. Silvetti S et al. ESC Heart Fail 2017 [ePub June 26].

22 June 2017

June 2017 post

Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach.

In these settings, levosimendan has potential advantages over conventional inotropes such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life (see paper).

A panel of 45 expert clinicians from 12 European countries met to review the literature and envision an appropriately designed and properly powered clinical trial addressing these needs. A composite Global Rank Score was advocated as primary end-point where death, re-hospitalization, and change in N-terminal prohormone-brain natriuretic peptide level are considered in a hierarchical order (see previous FIGHT trial).

22 June 2017

May 2017 post

From April 29 to May 2 at the Palais des Congrès in Paris, the Heart Failure Association of the European Society of Cardiology held its annual meeting.

Within the program, I highlight a series of eleven 30-minutes hands-on tutorials on the use of the inodilator levosimendan in acute and advanced heart failure which were structured in several sessions touching the therapeutic needs and options, the comorbidities, the scientific evidence, the guidelines, and the clinical practice.

The take home message was that the inidilator levosimendan is a safe and valid therapeutic option for patients in advanced heart failure. Chairs and lecturers were from Austria (G.Pölzl, J.Altenberger), Italy (G.Malfatto), Hungary (Z.Papp), Finland (V.-P.Harjola, M.Kivikko), Sweden (K.Karason), Greece (J.Parissis), Denmark (F.Gustafsson), and Germany (D.Kindgen-Milles, C.Tschöpe).

The eleven lectures were collected on tape and can be now seen in YouTube format on a new dedicated educational channel (EPGonline Acute and Advanced Heart Failure)