After establishing the diagnosis, both pharmacological and, if needed, non-pharmacological treatment should be initiated as soon as possible. Timing remains a critical issue in the treatment of acute heart failure; the latest American and European guidelines both recommend immediate administration of diuretics if the patient shows congestive symptoms (Yancy et al., 2013; Ponikowski et al., 2016). However, the evidence surrounding the timing of treatment regarding patient outcomes is limited and much of the existing literature is based on retrospective data and expert opinions. Results recently published from the Registry Focused on Very Early Presentation and Treatment in Emergency Department of Acute Heart Failure (REALITY-AHF) study have highlighted that timing of treatment administration not only has an impact on mortality, but there may also be an optimum treatment window. The study was the first prospective, multicentre registry study to focus on the timing of treatment in the very acute phase of heart failure. A total of 1,291 patients with acute heart failure were recruited from 20 hospitals in Japan and monitored over the 48 hours following emergency department admission, for vital signs and treatment timings. All patients received intravenous furosemide within 24 hours of admission, however those who received treatment in the early phase (within 60 minutes) had significantly lower in-hospital mortality rates compared to the non-early treatment group (2.3% vs. 6%, p=0.002). The results of this study shed light on both clinical practice and clinical trials as previous studies for novel treatments have often failed to show beneficial prognostic outcomes which may be due to the timing of treatments (Kagiyama & Matsue, 2018).
Although further studies are required, initial results suggest that treatment within 6 hours of admission is likely to change the clinical course of acute heart failure (Kagiyama & Matsue, 2018).
Treatment approach is dependent on how the patient presents. For example: inadequate oxygenation, life-threatening arrhythmias, low blood pressure (<90 mmHg) or cardiogenic shock, acute coronary syndrome and acute mechanical causes all require different management strategies.
Despite improvements in treatment, acute heart failure continues to have high rates of morbidity and mortality. Seeking to address this, the European Society of Cardiology – Acute Cardiovascular Care Association recently called for greater interdisciplinary care. The recommendations highlight the fragmentation of care many patients experience as a consequence of the multiple specialities involved in their management. The recommendations stress that an integrated care plan, based on the hospital’s resources and experience, is essential to drive improved and consistent care. While the recommendations made the call for greater interdisciplinary care, it also highlighted a series of gaps that require improvement. These included the need for early diagnosis and treatment, identification of an appropriate disposition for the majority of patients who do not require treatment in the intensive care unit at presentation, improvement in the diagnosis of accompanying acute myocardial infarction, and better assessment of intravascular volume status, which many physicians continue to perform suboptimally (Mueller et al., 2017).
In addition to provision of timely and effective treatment through interdisciplinary care, the inclusion of comprehensive inpatient monitoring is essential to optimising the management of patients with acute heart failure. The Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology recently released a statement outlining a recommended approach to utilising monitoring tools to enable improved decision making (Figure 14). With physicians under pressure to reduce hospital length of stay while preventing subsequent hospital visits, morbidity and mortality, the use of improved monitoring techniques may help them to achieve these goals (Harjola et al., 2018).
Intravenous loop diuretics (e.g. furosemide) are the cornerstone of treatment of congestion in patients with acute heart failure and are recommended for all patients with signs or symptoms of fluid overload. A furosemide bolus dose of 20–40 mg is recommended (Felker et al., 2011; Harjola et al., 2017; Shah et al., 2017). Guidelines recommend that treatment should be initiated as soon as possible, and early treatment has been shown to improve patient outcomes (Ponikowski et al., 2016; Mueller et al., 2017). A prospective study of 1,291 acute heart failure patients revealed that the mean door-to-furosemide (i.e. time from arrival at the emergency department to receival of first dose of furosemide) in the centre was 90 minutes. However, patients who received early treatment (door-to-furosemide <60 minutes) had significantly lower in-hospital mortality than patients who did not receive early treatment (2.3% vs. 6.0%, p=0.002), and this remained significant in multivariate analysis (OR 0.39, 95% CI 0.20–0.76, p=0.006) (Matsue et al., 2017). However, not all patients respond equally to loop diuretics and treatment may need to be modified. Analysis of patient data from the NHLBI Heart Failure Network ROSE-AHF and CARRESS-HF trials revealed that patients with a reduced fluid output, weight loss and response to diuretics was associated with increased 6-day mortality. Interestingly, elevated baseline cystatin C, a biomarker for renal dysfunction, was associated with a reduced diuretic response and, therefore, patients with renal insufficiency require higher doses of loop diuretics to achieve therapeutic decongestion (Kiernan et al., 2018).
Aside from intravenous loop diuretics, intravenous vasodilators (nitrates, nitroprusside) are also helpful in relieving symptoms in patients with a systolic blood pressure >90 mmHg. Vasodilators are often used in acute heart failure for patients who are hypertensive or have pulmonary oedema (Shah et al., 2017). However, robust data on their effect on outcomes are limited (Wakai et al., 2013; Harjola et al., 2017).
Table 3. Vasodilators used to treat acute heart failure (Ponikowski et al., 2016)
Positive inotropic agents (dopamine, dobutamine, milrinone, levosimendan) are another treatment option, however according to the current European guidelines (Ponikowski et al., 2016; Harjola et al., 2017) these "should be reserved for patients with a severe reduction in cardiac output resulting in compromised vital organ perfusion". It is further stated that levosimendan should be preferred over dobutamine to reverse the effect of beta-blockade (Mebazaa et al., 2009). Some of the pharmacological differences observed between levosimendan and other inotropic agents are believed to be a consequence of it acting as a calcium sensitiser, rather than a calcium mobiliser, meaning cardiomyocytes are not exposed to high levels of ionic calcium and the resulting increase in myocardial oxygen consumption (Alternberger et al. 2018). The recommended dose of levosimendan is an optional bolus of 12 μg/kg over 10 min, followed by a continuous infusion of 0.1 μg/kg/min, which can be decreased to 0.05 or increased to 0.2 μg/kg/min (Ponikowski et al., 2016).
Table 4. Positive inotropes and/or vasopressors used to treat acute heart failure (Ponikowski et al., 2016)
A recent essay submitted to the European Heart Journal Supplements summarised the benefits of levosimendan for treatment of acute and advanced heart failure following a series of tutorials presented at the 2018 European Society of Cardiology Congress. The first-in-class inodilator is well regarded as one of the treatment options when standard therapies fail or when systematic haemodynamics, organ perfusion and function may be at risk as the treatment exerts enhanced cardiac contractility as well as vasodilator and cardioprotective effects. In addition, compared with catecholaminergic inotropes, levosimendan differs greatly in pharmacological efficacy and safety, as there is no indication that levosimendan shortens life. Due to this, there is a view that general ‘de-catecholaminisation’ of unstable and critically ill patients should be a goal. Furthermore, the long duration of action (~7 days) may be beneficial for intermittent use in long-term management. It has been suggested that if the progression of heart failure is intervened to restore equilibrium in between the start of a phase of deterioration and hospitalisation, health-related quality of life could improve significantly (Crespo-Leiro et al., 2018; Pölzl, 2018).
A position paper from 35 European experts examined the role of levosimendan – aiming to compile the evidence behind it and its potential use in less established settings. They noted that levosimendan improved left ventricular diastolic function, attenuated cardiac remodelling, increased coronary blood flow, helped to improve ventriculo-arterial coupling (the relationship between the myocardial contractility and arterial afterload), and may have a protective effect on the myocardium against ischaemia as investigated in animal models and some clinical studies with a limited number of patients (Papp et al., 2012). Clinical trials demonstrated beneficial anti-inflammatory effects in heart failure patients. They suggested that more evidence was required, but from these physiological findings as well as other data demonstrating the impact on organ systems, the drug is expected to have beneficial effects on other conditions associated with acute heart failure (Farmakis et al., 2016). A meta-analysis examining the use of levosimendan in patients with acute right heart failure indicated that levosimendan has short-term efficacy, increasing ejection fraction and tricuspid annular plane systolic excursion while significantly reducing systemic pulmonary artery pressure and pulmonary vascular resistance (Qiu et al., 2017). Another meta-analysis in patients with acute decompensated heart failure showed that treatment with levosimendan reduced brain natriuretic peptide versus control groups (except dopamine), improved LVEF and increased heart rate compared with before administration (Zhou et al., 2018). It is believed to confer these effects by increasing the sensitivity of cardiomyocyte troponin C fibres to ionic calcium and by acting on potassium-dependent ATP channels on cardiac mitochondria and vascular smooth muscle cells (Altenberger et al., 2018).
Another position paper by a panel of 34 European experts recommend the use of levosimendan in patients with acute heart failure and/or cardiogenic shock complicating acute coronary syndrome depending on the presence of congestion, levels of blood pressure and heart rate, and the extent of cardiac ischemia. Levosimendan can be used alone or in combination with other agents, but it requires continuous monitoring due to the risk of hypotension (Nieminen MS et al., 2016). Harjola et al., have also discussed a number of clinical trials surrounding the use of levosimendan in acute heart failure and have suggested that based on the haemodynamic effects and safety profile in clinically unstable patients, levosimendan should be considered more often as a preferable alternative to conventional adrenergic inotropes (Harjola et al., 2018).
The benefits and applications of levosimendan may go further than acute heart failure, as some studies have shown cardioprotective effects against low cardiac output (LCO) syndrome postoperatively. However, two large randomised clinical trials, CHEETAH and LEVO-CTS, were unable to identify any benefit of levosimendan in comparison to placebo for survival, which has reignited the debate surrounding its use in this setting (Landoni et al., 2017; Mehta et al., 2017). A post-hoc analysis from LEVO-CTS on patients to who had undergone coronary artery bypass grafting (CABG) surgery (66% of the patients) revealed that levosimendan improved 90-day survival significantly compared to placebo group (2.1% vs. 7.9%, p=0.0016). This was accompanied with a significant improvement in postoperative cardiac index, in the frequency of LCOS and in the need for further inotropic support (Guarracino et al., 2018). Following the results of these trials, Tena and colleagues carried out a systematic review and meta-analysis which included 14 randomised controlled trials with a total of 2,243 patients. The analysis revealed an overall reduction of 29% in 30-day mortality in the levosimendan group compared to controls (6% vs. 8.6%, RR = 0.71: 95% CI, 0.53–0.95; p=0.023). A significant reduction in renal replacement therapy rate was also observed in the levosimendan group compared to the control group (p=0.015). Levosimendan also appeared to reduce the incidence of LCO compared to controls (14.8% vs. 29%, RR = 0.40: 95% CI, 0.22–0.73; p=0.003). However, the results remain uncertain as the majority of the studies included in this meta-analysis used small sample sizes, whereas the more recent studies to show no benefit were much larger in nature (Tena et al., 2018). Another meta-analysis concluded that based on the more recent results from the LEVO-CTS, CHEETAH, and LICORN studies, levosimendan can’t be recommended as a standard therapy for cardiac surgery at this stage and further studies are needed to clarify this debate (Santillo et al., 2018).
In patients with cardiogenic shock unresponsive to inotropic agents, an intravenous vasopressor (noradrenaline preferably, or dopamine) can be given (De Backer et al., 2010).
When vasopressors or inotropic agents are used, blood pressure and ECG should be closely monitored, as they may cause arrhythmias or ischaemia. Levosimendan has been used in cardiogenic shock whenever blood pressure is ensured by noradrenaline.
Mechanical circulatory support, extracorporeal oxygenation (ECMO), ultrafiltration and renal replacement therapy may be useful in selected patients. Short-term mechanical support can be considered in patients with cardiogenic shock refractory to other treatments (Ponikowski et al., 2016).
Oxygen is commonly used in patients with dyspnoea, however, supplemental oxygen has been shown to cause a fall in cardiac output and increase systemic vascular resistance and cardiac filling pressures. Therefore, it should be reserved for patients who experience hypoxaemia. Instead, non-invasive positive pressure ventilation can reduce dyspnoea, heart rate, hypercapnia and in-hospital mortality (Shah et al., 2017).
Ultrafiltration (UF) can remove excess salt and fluid even if patients are resistant to high doses of diuretics. However, clinical studies of its use have shown mixed results with recent trials suggesting that UF offers no advantages over adjustable diuretic treatment, but with an increased number of adverse events. ESC guidelines recommend UF be considered in patients who fail diuretic therapy (Shah et al., 2017). The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) study indicated that UF was no more efficacious than an aggressive, urine-output guided pharmacological protocol for decongestion (Bart et al., 2012). However, to address issues with patient drop-out and treatment cross-over, a per-protocol analysis of the CARRESS-HF study was performed including only patients who were randomised to UF and had UF output collected or who were randomised to pharmacological treatment and had urine but not UF output collected. In this patient population, UF was associated with significantly higher cumulative fluid loss (P=0.003), net fluid loss (P=0.001) and relative reduction in weight (P=0.02) compared to the pharmacological treatment arm. UF was also associated with higher serum creatinine and blood urea nitrogen by 72 hours, lower serum sodium by 48 hours and increased plasma renin activity by 96 hours. However, no differences were observed in 60-day outcomes (Grodin et al., 2018).