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 ( 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 ( 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)