We listened with interest to a lively debate during the recent European Society of Cardiology (ESC) annual congress in Barcelona. The question under consideration was the role of inotropes in heart failure at large: “…are they dead and buried?” The answer that emerged from an amicable, but keenly contested exchange between Professor Milton Packer and Professor Gerhard Pölzl1 was that “…it depends on which inotrope and on which subtype of heart failure…” We summarize in this Comment some of the points that attracted our attention.

“Inotrope” is nowadays a much more sophisticated and capacious term than hitherto with a recent classification proposing a subdivision in the 3 categories of calcitropes, myotropes, and mitotropes2: (1) Calcitropes are drugs increasing contractility by an elevation of intracellular calcium, such as the beta-agonist dobutamine, the phosphodiesterase inhibitor milrinone, or the sodium pump inhibitor digoxin; (2) Myotropes are drugs increasing contractility by a direct interaction with the contractile proteins, such as the troponin C activator levosimendan or the myosin activator omecamtiv mecarbil; (3) Mitotropes are drugs that augment contractility by improving the efficiency of mitochondrial energy production: examples include the carnitine palmitoyltransferase-1 inhibitor perhexiline and the fatty acid oxidation inhibitor trimedazidine. Moreover – as a confounding factor - all the inotropes currently in clinical use have some pleiotropic effects, which may leave only the drug candidate omecamtiv in the “pure” inotrope box.

The definition of “heart failure” itself is now also broader than ever in both of its chronic and acute manifestations and reduced or preserved ejection fraction types. The chapters in the ESC Guidelines3 describing critical care subsettings such as cardiogenic shock and low cardiac output syndrome, and advanced heart failure with repetitive hospitalizations show how nuanced is the general term of “heart failure” in these days. Further complexities are introduced when the impact and influence of cardiac and noncardiac comorbidities (eg, cardiorenal syndrome, ischemic heart disease, arrhythmia, etc.) are also considered in an array of signs, symptoms, biomarkers, and clinical manifestations.

Given the highly granular new classification of “heart failure”—made possible by the above extensions to the definition—it will come perhaps as no great surprise that none of the established inotropes have been studied comprehensively in any closely-defined heart failure subsetting so far.4

The potential consequences of this deficit for patient treatment, drug discovery, and drug development are clearly illustrated by the experience with the recent GALACTIC-HF study.5 In this large trial, more than 8000 patients with chronic heart failure with reduced ejection fraction were randomized to receive omecamtiv mecarbil or placebo. The difference in the outcome for the composite primary endpoint (hospitalization or urgent visit for heart failure, or death from cardiovascular causes) was (just about) statistically significant (P = 0.03), but the absolute risk reduction between the groups was of debatable clinical relevance and placed a question mark over the drug's future. Post hoc analyses from the GALACTIC-HF trial revealed that the impact of omecamtiv mecarbil was greater in patients with lower ejection fraction and lower systolic blood pressure6 than in patients with higher ejection fraction and higher systolic blood pressure. Nevertheless, the representativeness of the patients in such a subgroup was debated.7 These insights illustrate that a more exact definition of HF and correspondingly rigorous selection of patients a priori might have produced a clearer path for the clinical use of omecamtiv mecarbil.

This has been a recurring theme with inotropes during their regulatory clinical developments as further evidenced; for example, for levosimendan in the REVIVE study in acute HF: the recruitment of hypotensive patients to that trial may be seen in hindsight as a misjudgement that compromised the drug's development path at least in the USA.8

By limiting the spectrum of the heart failure pathology considered, a more realistic, effective, and successful use of inotropes in heart failure may be achieved, albeit the population of potential recipients may be reduced in size. As an example, we nominate the use of repeated cycles of levosimendan therapy in advanced heart failure. In his presentation at the ESC debate, Professor Pölzl1 identified 10 trials with a control arm—and mortality among the end points—that are suggestive of a survival benefit (Fig. 1). Moreover, levosimendan has been in clinical use for over 20 years across a range of acute settings,9 including acute and advanced heart failure, cardiac surgery, cardiogenic shock, and Takotsubo syndrome. Indications of its benefit have repeatedly been identified in meta-analyses, but not always to the level of statistical significance, possibly because the initial trials did not precisely identify those patients best placed for inclusion.

FIGURE 1.: Meta-analysis of the 10 published trials with control-arm and describing mortality effects of levosimendan on top of standard of care1 (with permission).

In accordance, recent trials post-hoc analyses showed how the prophylactic use of levosimendan can reduce mortality in patients with low cardiac output syndrome undergoing isolated CABG.10 Based on these new data, we would not dissent with the assessment that “levosimendan cannot be at the moment recommended for routine use in all [our emphasis] cardiac surgery settings,”11 but these same data also once more hint at how precise targeting of treatment to some well-defined subsets of patients may yield greater therapeutic benefits than are apparent in the aggregate findings of even well-structured clinical trials. Proceeding from the experiences outlined above, we see a future for levosimendan in advanced heart failure and in well-defined acute manifestations, for example, to wean patients from VA-ECMO, or as bridge to devices or transplant, or just to preserve viable cardiac and hemodynamic functions giving time for health care professionals to identify longer-term solutions.

In conclusion, we suggest refinements for the recommendations of inotropic drug applications. Collectively, the challenge for clinical researchers is to identify the relevant subsets of patients. This may involve trials that produce even “negative” or inconclusive results to identify hypothesis-generating findings for the definition of prospective subgroups with the desired clinical perspectives.

All in all, all observations with inotropes have contributed to the emergence of a “right patient–right drug” paradigm for the selection of such therapy, that starts by enquiring whether an inotrope is needed at all before selecting one, based on the specific clinical presentation12 and then by acting with pragmatism.13 We too see a future for inotropes more generally in various selected subgroups of heart failure, provided the necessary investment is made to identify and characterize those subgroups for individual drugs such as dobutamine, milrinone, levosimendan, and possibly omecamtiv mecarbil. We must not throw the baby out with the bath water, just because in the past the clinical trials were not focused enough.

1. Pölzl G. Lecture at the GREAT DEBATE on “Inotropes for the treatment of heart failure remain dead and buried?”. ESC 2022 Congress, Barcelona, August 27, 2022. Available at: https://esc365.escardio.org/presentation/243810?resource=video. Accessed September 15, 2022. 2. DesJardin JT, Teerlink JR. Inotropic therapies in heart failure and cardiogenic shock: an educational review. Eur Heart J Acute Cardiovasc Care. 2021;10:676–686. 3. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–3726. 4. Pollesello P, Ben Gal T, Bettex D, et al. Short-term therapies for treatment of acute and advanced heart failure-why so few drugs available in clinical use, why even fewer in the pipeline? J Clin Med. 2019;8:1834. 5. Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384:105–116. 6. Teerlink JR, Diaz R, Felker GM, et al. Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALACTIC-HF. J Am Coll Cardiol. 2021;78:97–108. 7. Mefford MT, Koyama SY, De Jesus J, et al. Representativeness of the GALACTIC-HF clinical trial in patients having heart failure with reduced ejection fraction. J Am Heart Assoc. 2022;11:e023766. 8. Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail. 2013;1:103–111. 9. Papp Z, Agostoni P, Alvarez J, et al. Levosimendan efficacy and safety: 20 years of SIMDAX in clinical use. J Cardiovasc Pharmacol. 2020;76:4–22. 10. Caruba T, Charles-Nelson A, Alexander JH, et al. Prophylactic levosimendan in patients with low ejection fraction undergoing coronary artery bypass grafting: a pooled analysis of two multicentre randomised controlled trials. Anaesth Crit Care Pain Med. 2022;41:101107. 11. Guarracino F, Heringlake M, Cholley B, et al. Use of levosimendan in cardiac surgery: an update after the LEVO-CTS, CHEETAH, and LICORN trials in the light of clinical practice. J Cardiovasc Pharmacol. 2018;71:1–9. 12. Bistola V, Arfaras-Melainis A, Polyzogopoulou E, et al. Inotropes in acute heart failure: from guidelines to practical use: therapeutic options and clinical practice. Card Fail Rev. 2019;5:133–139. 13. Farmakis D, Agostoni P, Baholli L, et al. A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: an expert panel consensus. Int J Cardiol. 2019;297:83–90.