Facing up to the challenges of acute heart failure

The term ‘acute heart failure’ (AHF) describes a situation of rapid onset or worsening of symptoms and/or signs of heart failure (HF). It is a life-threatening medical condition requiring urgent evaluation and treatment, typically leading to urgent hospital admission.¹

So far, so simple. This summary description conceals, however, a very complex and clinically challenging scenario which remains one of the major challenges of cardiology practice despite many decades of earnest and vigorous research directed at both the causes of AHF and the means of its treatment.

It has been estimated that there are more than 1 million hospitalizations for HF each year in the USA alone and that patients hospitalized with HF have the highest 30-day readmission rate (25%) of any diagnosis, with more than 50% of patients being readmitted within 1 year; multiple readmissions are not uncommon. Data from the ESC HF Long-Term Registry (N = 12 440) indicate a 1-year rate of death or re-hospitalization of about 36% in AHF patients—more than double that seen in cases of chronic HF. Marked and notable variations around that central estimate have been identified based on initial presentation (e.g. 54.0% 1-year mortality in cardiogenic shock vs. 12.8% in hypertensive HF) and according to systemic blood pressure at first presentation,² data that reaffirm that ‘AHF’ is not a unitary entity and highlight the importance of a clear grasp of underlying pathophysiology in each individual case.

Given the expense inherent in any hospital admission it can be no surprise to discover that hospitalizations account for by far the single largest documented component of direct costs associated with AHF management. The estimated mean cost of hospitalizations with primary HF in the USA in 2014 approximated $11 billion;³ costs of $53 billion are projected for 2030, mostly accruing to hospital-related costs. In Greece, where about one in four hospitalized patients dies and four in 10 are re-hospitalized within a year, mean annual economic cost per patient exceeds €4400, of which about two-thirds is attributable to the costs of inpatient care.⁴ Most health-care systems in developed and industrialized countries return similar findings: AHF is a very substantial cause of hospital-related costs.

These financial figures are unpalatable but ultimately are matters of greater concern, arguably, to health service administrators, policymakers and perhaps tax-payers than they are to clinicians. The same cannot be said for the observation that HF-attributed mortality has stopped declining.⁴ Comparisons with cancer might be regarded as tendentious but it is hard to reject that this comparison appears to indicate that progress in the management of HF really does seem, at least at the aggregate level, to have tracked sideways in recent decades.⁵

Detailed examination of the possible reasons for this trend are beyond the scope of an Editorial but observations emerging from the ‘Get With the Guidelines-Heart Failure' (GWTG-HF) programme provide some pertinent and not infrequently chastening insights, including important disadvantaging of hospitalized patients who have renal dysfunction⁶ despite clear indications that renal dysfunction is a widely prevalent comorbidity associated with higher mortality rates than in ‘uncomplicated’ AHF. The fact that this initiative is named ‘Get With the Guidelines’⁷ leaves little to the imagination when trying to ascertain some of the reasons for the recent relative lack of progress in AHF management.⁸

Lack of success in the development of new medical therapies for AHF has also contributed. Various promising drugs for AHF with reduced ejection fraction have emerged in preclinical models and small Phase 2 trials, but with few exceptions those have failed to meet the primary endpoints in larger Phase 3 trials. A lively debate currently surrounds what constitutes an appropriate endpoint for such studies—in particular whether long-term mortality, an outcome much valued (not without good reason) by regulatory authorities is an appropriate and informative measure of the value and utility of a short-term therapy: even long-established therapies have failed to meet that standard⁹ and, by way of an alternative, it might be argued that prevention of decompensation and reducing hospital admissions are more pertinent goals or that greater attention should be given to stabilizing patients during the vulnerable post-discharge period in order to prevent re-hospitalization.¹⁰

No single agent either available or anticipated can be expected to be a panacea for a condition as complex and physiologically multifaceted as AHF. Within the class of inotropes and inodilators, however, levosimendan attracts attention as an important mechanistic departure from adrenergic stimulation as a means to enhance cardiac contractility and output without a mortality penalty.¹¹ In several scenarios of AHF, including situations of renal complication, levosimendan-associated vasodilator effects, mediated via ATP-dependent potassium channels, are also pertinent to the evaluation of its overall clinical impact. These considerations are addressed in the contributions to this supplement, which provide context and some practical guidance on the deployment of inotropes and inodilators in general—and levosimendan in particular—in the management of AHF.

Funding

This paper was published as part of a supplement made possible by an unrestricted educational grant by Orion Pharma.

Conflict of interest: the author is employed at Orion Pharma and has been active in the discovery and development of the inodilator levosimendan.