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Acute and Advanced Heart Failure Blog

Professor Gerhard Pölzl is Chief of the Heart Failure and Heart Transplant Program at the Medical University Innsbruck. His research is focused on clinical studies in advanced and chronic heart failure and on translational studies in cardiomyopathies.

He has been Principal Investigator of the LevoRep clinical trial that tested the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure. He is now P.I. of the clinical trial LEODOR, on repetitive use of levosimendan in advanced heart failure.

This blog is focused on the therapeutic options for Acute and Advanced Heart Failure: new data, new studies, new opinions, new trends.


Latest posts

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.

 

References:

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.