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Eur J Heart Fail. 2019 Sep;21(9):1064-1078. doi: 10.1002/ejhf.1557. Epub 2019 Aug 13.

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

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Section of Cardiovascular Medicine, New Haven, CT, USA.
Center for Outcome Research & Evaluation (CORE), Yale University School of Medicine, New Haven, CT, USA.
Inova Heart & Vascular Institute, Falls Church, VA, USA.
Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany.
Division of Cardiology, School of Medicine, University of Colorado, Aurora, CO, USA.
San Francisco Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA, USA.
Cardiovascular and Cell Sciences Research Institute, St George's University of London, London, UK.
Vanderbilt Heart and Vascular Institute, Nashville, TN, USA.


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.


Chronic heart failure; Clinical trials; Inotropes


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