Istaroxime in Acute Heart Failure: The Holy Grail is at HORIZON?

Abstract

This article refers to ‘Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: a randomised, placebo-controlled trial’ by V. Carubelli et al., published in this issue on pages 1684–1693. Acute heart failure (AHF) is a complex clinical syndrome requiring hospitalization for urgent therapy and represents a significant burden to the healthcare system.1 Heart failure is responsible for more than 1 million hospitalizations per year both in Europe and in America.1 In addition, patients with AHF have a high 1-year mortality rate (25–30%) and experience multiple readmissions.2 Despite improving the initial signs and symptoms of AHF during hospitalization, current intravenous therapies have failed to reduce post-discharge event rates, and in some cases, may contribute to increased morbidity and mortality.3 Most AHF patients are treated with diuretics and vasodilators to alleviate congestion, while others may also receive inotropes and/or vasopressors. In AHF, inotropes are required for the treatment of the subset of patients with low cardiac output and resultant symptomatic hypotension and/or end-organ hypoperfusion.4 Overall, inotropes were used in 12% of patients admitted with AHF enrolled in the European Society of Cardiology Heart Failure Long-Term Registry, with higher proportions in those presenting with the ‘wet and cold’ profile (28%)5 or in those presenting with cardiogenic shock (81%).2 Inappropriate use6 as well as increasing short- and long-term term safety concerns7 have been reported regarding the use of inotropes and/or vasopressors in AHF. Clinical data collected on the effects of catecholamines, phosphodiesterase inhibitors and calcium sensitizers indicate an overall increase in mortality relative to usual care.8-11 Possible explanations for the increased mortality include increased myocardial oxygen consumption and a heightened propensity for cardiac arrhythmias,.8-11 In addition, the vasodilator properties may lead to hypotension, reduce coronary perfusion pressure, and predispose to arrhythmias.8-12 Given the lack of clear efficacy and the increase in mortality associated with existing inotropic agents used in AHF, there is a critical need for the development of inotropic therapy that relieves symptoms rapidly but does not increase mortality risk. Istaroxime is a novel pharmacologic agent with both inotropic and lusitropic properties and holds promise for the very difficult to treat high-risk patients with AHF presenting with low blood pressure.13 The inotropic effects of istaroxime are due to its ability to inhibit sodium–potassium adenosine triphosphate (Na–K ATPase), leading to an increase in cytosolic calcium concentration and thus improved contractility. The lusitropic effects are related to its ability to stimulate sarcoplasmic reticulum calcium ATPase isoform 2 (SERCA2), leading to rapid sequestration of cytosolic calcium back into the sarcoplasmic reticulum during diastole and thereby promoting myocardial relaxation.12 The greater calcium uptake in the sarcoplasmic reticulum allows increased release of calcium during systole, thereby increasing contractility. Results from animal experiments with istaroxime validate this favourable mechanistic profile by showing increased inotropy and accelerated relaxation without associated increased energy consumption or arrhythmias.12 In an animal heart failure model, a direct comparison of istaroxime and dobutamine suggests the change in dP/dtmax during treatment was similar between the two agents, but peak heart rate was significantly lower with istaroxime.14 Furthermore, using tissue Doppler, istaroxime improved myocardial relaxation (assessed by e′ diastolic velocity), when compared to dobutamine.14 In the HORIZON-HF (Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure) trial, 120 AHF patients with systolic blood pressure (SBP) of 90–150 mmHg were randomized 3:1 to receive istaroxime or placebo. Istaroxime was administered at 0.5, 1.0, and 1.5 μg/kg/min for 6 h, and serial haemodynamic assessments were performed.13 All three doses of istaroxime lowered pulmonary capillary wedge pressure, the primary study endpoint, by 3 to 5 mmHg compared with placebo. However, cardiac index increased only at the highest dose. The study confirmed prior animal studies that showed a significant decline in heart rate and shortening of the QTc interval (−29 to −49 ms) during treatment.12 A favourable lusitropic effect, as assessed by increased mitral deceleration time, occurred only at the highest dose.15 In this issue of the Journal, Carubelli et al.16 evaluated the effects of a 24 h infusion of two doses of istaroxime in patients hospitalized for AHF with left ventricular ejection fraction (LVEF) ≤40%. The study was a randomized, double-blind, placebo-controlled, parallel-group study, designed to evaluate the efficacy of two different doses of istaroxime (0.5 and 1.0 μg/kg/min) as compared to placebo. A total of 96 patients from China and 24 from Italy were randomly assigned to one of two doses of istaroxime or placebo delivered as an intravenous infusion over 24 h in a 2:1 ratio within two sequential cohorts of 60 patients each. Inclusion criteria included an ongoing hospitalization for AHF with dyspnoea at rest or on minimal exertion and need for intravenous diuretic therapy (>40 mg intravenous furosemide); SBP between 90 and 125 mmHg without signs or symptoms of peripheral hypoperfusion; intermediate to high E/e′ ratio by tissue Doppler echocardiography (>10); B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) plasma levels ≥350 pg/mL or ≥1400 pg/mL, respectively. The primary efficacy endpoint was the change from baseline to 24 h after the start of the infusion in the E/e′ ratio. In the intention-to-treat analysis, the mean change in E/e′ ratio at 24 h was −4.55 (4.75) in the istaroxime 0.5 μg/kg/min group vs. −1.55 (4.11) in the placebo cohort 1 group (P = 0.029) and − 3.16 (2.59) in the istaroxime 1.0 μg/kg/min group vs. −1.08 (2.72) in the placebo cohort 2 group (P = 0.009). Both istaroxime doses significantly increased stroke volume index compared with placebo, though the increase in LVEF did not reach statistical significance. There was a decrease in heart rate and an increase in SBP, which reached statistical significance with the 1.0 μg/kg/min dose. A favourable effect on renal function was observed with istaroxime, with an increase in the estimated glomerular filtration rate (eGFR) in the high dose group compared with placebo at 24 h. Self-reported dyspnoea and NT-proBNP changes showed no significant differences between istaroxime and placebo. Absolute troponin levels were not different with istaroxime treatment compared with placebo, and no major untoward effects, including arrhythmias were observed. The rate of serious adverse events did not show any significant differences in the three arms, although a numerical higher number was observed in the istaroxime 1.0 μg/kg/min group (n = 6, 15%). Adverse drug reactions, particularly gastrointestinal events, were more common with istaroxime treatment. The main efficacy result was the ability of a 24 h infusion of istaroxime to improve diastolic and systolic function parameters. While the changes were similar at both doses tested and better than placebo, these effects were seen without an increase in heart rate, unlike traditional inotropes. A sustained increase in SBP was observed with both doses of drug, reaching significance with the higher istaroxime dose. The results are comparable to those observed in the HORIZON-HF study,13 and the trend of E/e′ decrease parallels the trend in decrease in pulmonary capillary wedge pressure. Although other inotropes improve cardiac performance to a similar or greater extent than istaroxime, the main difference with this agent is the effect on blood pressure, heart rate and diastolic function. The fact that istaroxime caused a decrease in E/e′ while simultaneously increasing SBP is remarkable, given that increased afterload has previously been associated with decreased E′.17 An intriguing point is the absence of any association between NT-proBNP changes and treatment with istaroxime, association seen with most of the therapies able to improve cardiac performance.18 Future research studies, with larger sample size and/or longer duration of istaroxime infusion should elucidate this finding. End-organ damage, injury and subsequent dysfunction of target organs (i.e. heart, kidneys, liver) in the setting of AHF has been associated with increased risk for mortality.19 In the present study, there were no differences in troponin release after study drug infusion in either the istaroxime or placebo group.16 These findings suggest that istaroxime-induced improvements in diastolic function do not increase myocardial oxygen demand or increase myocardial damage. Along with improvement in renal function (increased eGFR), these effects suggest better organ protection, making the drug a potentially attractive option for the treatment of patients with hypotension and low cardiac output (Figure 1). The pharmacokinetic profile may also be beneficial in critically ill patients. With a very rapid onset of action and rapid washout after infusion termination (60 min half-time), this drug may be suitable for the use in critically ill patients. While istaroxime appears promising, future studies should look at infusion times longer than 24 h to prevent the abrupt reversal of the beneficial changes in vital signs (increase in heart rate and decrease in SBP) and echocardiographic parameters (increase in E/e′ and decrease in stroke volume index).16 This suggests a pronounced ‘rebound’ phenomenon, and may require a gradual discontinuation of istaroxime infusion rate. This study is now the second positive randomized controlled trial investigating the effect of istaroxime infusion in patients with AHF and reduced LVEF. In contrast to other available inotropic agents, the beneficial haemodynamic changes are associated with a reduction in heart rate and increases in SBP. In light of these properties, istaroxime appears to be a promising agent for patients presenting with AHF, particularly those with low SBP due to reduced cardiac output (Figure 1). However, further research is required to determine when istaroxime should be initiated and for what duration of time in this subset of AHF patients. Randomized studies of longer infusions of istaroxime, and comparing istaroxime with other available inotropic agents in patients with low cardiac output will further confirm the efficacy and safety profile of this therapy. Finally, larger studies will need to test the efficacy of istaroxime on post-discharge clinical outcomes such as AHF readmission and mortality in patients with borderline SBP or low cardiac output. Conflict of interest: O.C. received grants from Novartis, Servier and Vifor and participated in Advisory Board of Boehringer Ingelheim. S.P.C. has received grants from NIH, AHA, AHRQ, PCORI, Novartis, Bristol-Myers Squibb, Ortho Clinical; consulting fees from Roche, Relypsa, Boehringer Ingelheim, Ortho Clinical, Bristol-Myers Squibb. J.B. is a consultant for Abbott, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Relypsa, Vifor.

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