Interleukin-1 blockade in recently decompensated systolic heart failure: study design of the recently decompensated heart failure anakinra response trial (RED-HART)

Heart Failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, and poor exercise capacity due to impaired cardiac function. The incidence of HF is increasing and represents the leading cause of hospitalization in the United States among patients > 65 years of age. Neurohormonal blockade has proven to reduce morbidity and mortality; however the persistent toll of HF demonstrates the urgent need to continue to develop novel drugs that target other pathophysiological paradigms. The presence of inflammation in cardiovascular disease has been well-established and interleukin-1 (IL-1), the prototypical proinflammatory agent, has been shown in preclinical animal models to induce cardiac dysfunction. The current study will investigate the role of IL-1 as an inflammatory mediator of HF progression and investigate whether IL-1 blockade with anakinra, recombinant human IL-1 receptor antagonist, improves aerobic exercise performance in patients with recently decompensated systolic HF. This study will be composed of 3 treatment arms (20 patients each): 1) anakinra 100mg daily for 12 weeks; 2) anakinra 100mg daily for 2 weeks followed by placebo for 10 weeks; or 3) placebo for 12 weeks. All patients will be followed for at least 24 weeks. The co-primary endpoints will be placebo-corrected interval changes in peak oxygen consumption (VO2) and ventilatory efficiency (VE/VCO2 slope) measured by Cardiopulmonary Exercise Testing (CPX) after 2 weeks of anakinra treatment. Secondary endpoints will include interval changes in 1) CPX variables at 4, 12 and 24 weeks; 2) echocardiographic measures of cardiac dimension/function; 3) quality of life assessments; 4) inflammatory biomarkers; and 5) clinical outcome including days alive outside of the hospital and survival free of re-hospitalization for HF. The RED-HART study will be the first study to address the potential benefits of IL-1 blockade on aerobic exercise performance in patients with recently decompensated HF

Interleukin-1 blockade in heart failure with preserved ejection fraction: rationale and design of the Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2)

Heart failure with preserved ejection fraction (HFpEF) now accounts for the majority of con-firmed HF cases in the United States. However, there are no highly effective evidence-basedtreatments currently available for these patients. Inflammation correlates positively withadverse outcomes in HF patients. Interleukin (IL)-1, a prototypical inflammatory cytokine, hasbeen implicated as a driver of diastolic dysfunction in preclinical animal models and a pilot clini-cal trial. The Diastolic Heart Failure Anakinra Response Trial 2 (D-HART2) is a phase 2, 2:1 ran-domized, double-blind, placebo-controlled clinical trial that will test the hypothesis that IL-1blockade with anakinra (recombinant human IL-1 receptor antagonist) improves (1) cardiorespi-ratory fitness, (2) objective evidence of diastolic dysfunction, and (3) elevated inflammation inpatients with HFpEF (http://www.ClinicalTrials.gov NCT02173548). The co–primary endpointswill be placebo-corrected interval changes in peak oxygen consumption and ventilatory effi-ciency at week 12. In addition, secondary and exploratory analyses will investigate the effectsof IL-1 blockade on cardiac structure and function, systemic inflammation, endothelial function,quality of life, body composition, nutritional status, and clinical outcomes. The D-HART2 clinicaltrial will add to the growing body of evidence on the role of inflammation in cardiovascular dis-ease, specifically focusing on patients with HFpEF

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure: Results From REDHART (Recently Decompensated Heart Failure Anakinra Response Trial)

An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of IL-1 (interleukin-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF