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Wheels of Fortune or Walking Dead?

Felix Schönrath, MD
Evgenij V. Potapov, MD, PhD

Deutsches Herzzentrum Berlin
Berlin, Germany

Is sacubitril valsartan the future of heart failure medicine or simply futile medicine in end-stage heart failure patients?

Since the PARADIGM HF study in 2014 showed remarkable improvements in outcome of heart failure patients with sacubitril valsartan, an angiotensin receptor neprylisin inhibitor (ARNI), this combined drug therapy has been at the center stage of heart failure medicine. Therefore, heart failure guidelines from both the US and from Europe launched in 2016 recommend this drug combination for the treatment of symptomatic heart failure patients.

Many promises and desires were associated with the first new heart failure drug therapy for fifteen years. But is it really possible to improve outcome in such a way that other end-stage heart failure treatment strategies will step back and be useless in comparison?

The PARADIGM HF trial included patients with NYHA class II to IV but only a minority were in class IV (60 patients) and results were not significant for these patients. Beside an overwhelming body of literature addressing ARNI therapy for chronic heart failure that has arisen since 2014, not a single article directly addresses the problem of acute heart failure. Therefore, a statement concerning the patients with most severe, and in many cases acute, heart failure seems to be questionable. But for these patients who are at highest risk and often receive an assist device in an emergency or at least urgent procedure, sophisticated treatment algorithms are needed. In this situation one can assume that trials with therapies that are administered in this setting of acute heart failure, such as dobutamine, milrinone or levosimendan, would gain more insight into necessary treatment strategies in this patient cohort. In view of this further delay in finding a definitive treatment, strategies like VAD surgery or heart transplantation could influence outcome in a negative direction, e.g. if right heart function worsens or end-organ failure arises. Another more practical problem we are facing in this acute and often end-stage heart failure patient cohort nowadays is that with a new drug combination like sacubitril valsartan the lack of awareness of the pharmacological activity on the part of some more general health care providers is a relevant issue. This has led to patients ending up with diuretic therapy only, because sacubitril valsartan was stopped due to worsening of renal function. That this was because of the wanted natriuretic effect and the wanted blood pressure lowering was not taken into account. If this happens, other drugs like diuretics need to be reduced but, as always, the new kid on the block is first blamed for the problems and reluctance toward change may increase. This is different to the situation with well-established therapies with ACE inhibitors or ARBs where everybody is aware of this effect.

But is this enough reason to be hesitant in treating end-stage heart failure patients with ARNIs and is there at least some data tackling this problem?

A post hoc analysis of the Paradigm HF data presented by Scott Salomon in 2016 (Circ Heart Fail, March 2016) showed an effect of sacubitril valsartan on mortality and hospitalization independent of the baseline left ventricular ejection fraction. In this analysis a relevant number of patients (>1200) had a most severely impaired left ventricular ejection fraction (less than 22.5%).

Another analysis by Milton Packer published in 2015 in Circulation tackled concerns that are important in acute heart failure. He showed shorter ICU stays (-18%) and less use of positive inotropic substances (-31%) in patients on sacubitril valsartan. Astonishingly, Kaplan-Maier curves for hospital admission diverged after 5-10 days following randomization and differed significantly after 30 days, supporting the assumption of acute effects of this drug combination.

With this glimpse of data and being aware of the formal contraindication for sacubitril valsartan in patients with acute heart failure, under close monitoring it could become an additional arrow to tackle this disease in selected patients. For example, patients with high systemic vascular resistance in an acute setting or patients with chronic low cardiac output, if the blood pressure allows the treatment, could possibly benefit. At least acute heart failure patients should be included in upcoming trials in efforts to hopefully further decrease the burden of this epidemic disease.

The "heart team" is en vogue and is required for many invasive procedures such as PCI or TAVI. In our opinion, the use of new potent heart failure drugs versus LVAD -Implantation in patients with acute or severe chronic heart failure should also be regularly discussed in a "heart failure team" consisting of a heart failure cardiologist and heart failure cardiac surgeon. At the least, the treatment with those drugs should be initiated and monitored in centers running a VAD or HTx program. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.

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