Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials

Abstract

Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti‐hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long‐term use in heart failure. The focus of this state‐of‐the‐art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients.

Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial

“…[4][5][6][7] In addition, chronic therapies directly targeting the myocardium are lacking and prior attempts have been fraught with safety concerns owing to dependency on Ca 2+ and/or second-messenger signalling. 2,3,8,9 A new drug class, direct cardiac myosin activators or myotropes, offers the potential to circumvent these prior limitations. 10 Danicamtiv (formerly MYK-491) is a novel small molecule that selectively enhances cardiac actomyosin activity, the molecular force-generating unit of the sarcomere, prolonging contraction while preserving actin-myosin detachment, allowing relaxation, and without impacting Ca 2+ homeostasis.…”

September 2020 at a glance: focus on heart failure with preserved ejection fraction and medical therapy

“…Inotropic drugs did not improve survival in HF. 17,18 Better results can be expected from drugs not acting through an increase in intracellular calcium. Danicamtiv, a novel cardiac myosin activator, improved stroke volume, global longitudinal and circumferential strain and left atrial function in experimental models and in a phase 2a trial in patients with HFrEF.…”

Targeting Orai1-Mediated Store-Operated Ca2+ Entry in Heart Failure

“…However, the use of positive inotropic drugs has been plagued by serious concerns regarding increased morbidity and mortality. Problems include increased atrial or ventricular arrhythmias, induced myocardial ischemia, and in some cases, arterial hypotension ( Ahmad et al, 2019 ). Moreover, long-term use of conventional inotropic agents has been associated with no improvement in overall mortality ( Ahmad et al, 2019 ).…”

“…Problems include increased atrial or ventricular arrhythmias, induced myocardial ischemia, and in some cases, arterial hypotension ( Ahmad et al, 2019 ). Moreover, long-term use of conventional inotropic agents has been associated with no improvement in overall mortality ( Ahmad et al, 2019 ). There is a possibility that the adverse effects of inotropic agents could promote pump failure as well as arrhythmias via dysfunctional Ca 2+ cycling.…”