Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study

Tassell, Benjamin Van; Mihalick, Virginia; Thomas, Georgia; Marawan, Amr; Talasaz, Azita Hajhossein; Lü, Juan; Kang, Le; Ladd, Amy C.; Damonte, Juan Ignacio; Markley, Roshanak; Turlington, Jeremy; Federmann, Emily; Buono, Marco Giuseppe Del; Biondi‐Zoccai, Giuseppe; Canada, Justin M.; Arena, Ross; Abbate, Antonio

doi:10.1186/s12967-022-03466-9

Cited by 15 publications

(22 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The role of IL-1β production in adapting heart function to both sterile and infectious inflammatory conditions has been extensively described in the literature ( 7 , 32 , 33 ). An ongoing phase 2 clinical trial is even assessing the therapeutical potential of IL-1R blockade with anakinra to treat heart failure ( 34 ). Along with TNF and IL-6, IL-1 (not mature IL-1β) was indicated as a factor involved in delayed repolarization, long QT syndrome, and ventricular tachycardia ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

IL-1β is not critical to chronic heart dysfunction in mice with Chagas disease

et al. 2022

View full text Add to dashboard Cite

Long after Trypanosoma cruzi infection, 40% of individuals develop a progressive chronic chagasic cardiomyopathy (CCC), with systolic dysfunction and arrhythmias. Since we previously showed IL-1β mediates the development of systolic dysfunction and cardiac arrhythmias in diabetes mellitus and cardiorenal syndrome, and IL-1β remains elevated in Chagas disease patients, here we tested the role of IL-1β in CCC using a mouse model. Mice deficient in IL-1R expression (Il-1r−/−) survived acute T. cruzi infection with greater parasitemia than controls but did not lose weight as wild-type (WT) did. At the chronic stage, WT presented prolonged ventricular repolarization intervals (QJ), while Il-1r−/− presented intervals like noninfected controls. Infected Il-1r−/− and WT did not differ in stroke volume (SV), the incidence of cardiac arrhythmias on electrocardiography (EKG), whole heart action potential duration (APD), or the incidence of triggered activity after S1–S2 protocol, which is a measure of susceptibility to cardiac arrhythmias. We also treated chronically infected WT mice with an IL-1R antagonist, anakinra. Treatment shortened the QJ interval but did not improve the SV or the incidence of cardiac arrhythmias on EKG. Anakinra failed to reduce triggered activity following the electrical extra-stimulation protocol. In conclusion, the absence of functional IL-1β/IL-1R signaling did not prevent or reverse the decrease of SV or the incidence of cardiac arrhythmias induced by chronic T. cruzi infection, implying this is not a critical mechanism in generating or maintaining CCC. Since similar cardiac abnormalities were previously credited to IL-1β signaling, ruling out this mechanism is important to discourage further attempts of IL-1β blockade as a therapeutical measure.

show abstract

Section: Discussionmentioning

confidence: 99%

IL-1β is not critical to chronic heart dysfunction in mice with Chagas disease

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Van Tassell et al (2022) is an ongoing trial that is measuring CRP as an outcome, but the current trial data only provided a theoretical description of the biomarker levels and could not provide numerical data (in terms of mean +/− SD) that could be used in our analysis, similar to other studies. Hence, it could not be included for analyzing the effect of anakinra on CRP [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…Despite the modest change due to anakinra, the peak VO 2 was considered significant in their results. On the contrary, in a REDHART trail, anakinra treatment for 2 weeks had no significant difference but, with continued treatment at 4 and 12 weeks, was associated with an improved peak VO 2 relative to the baseline values [ 30 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…This correlates with one study that showed no infections in the anakinra group compared to 12 AEs among ten patients in the placebo group [ 29 ]. Furthermore, despite the occurrence of adverse events, data collected from the Duke Activity Status Index (DASI) and Minnesota Living with Heart Failure Questionnaire (MLWHFQ questionnaires) indicated a positive change in functional capacity restoration in the anakinra group compared to the placebo group [ 31 , 32 ]. Similarly, a significant improvement in DASI was also recorded in the anakinra group [ 28 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anakinra in Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

et al. 2022

View full text Add to dashboard Cite

Background: Heart failure (HF) has become increasingly difficult to manage given its increasing incidence. Despite the availability of novel treatment target relieving inhibition and congestions for neurohormonal activation, heart failure is one of leading health conditions associated with high hospitalization and readmission rates, resulting in poor quality of life. In light of this, this article serves to demonstrate the effect of anakinra as one of the treatment paradigms for HF to explore the need for advanced novel interventions. Methods: We conducted a search in five electronic databases, including Embase, MEDLINE, Cochrane, Scopus, and PubMed, for RCTs (randomized controlled trials) evaluating the effects of anakinra against placebo in HF. Meta-analysis was performed using RevMan version 5.4. Results: Eight RCTs were obtained and included for analysis in this study. The results demonstrate that anakinra significantly reduces the levels of CRP (C-reactive protein), with significant difference between anakinra- and placebo-treated groups. Analyses also show that CRP failed to cause an improvement in peak oxygen consumption and ventilatory efficiency. Additionally, the treatment-related adverse events were insignificant. Some considerable limitations are that the same set of researchers were involved in most of the studies; hence, more independent studies need to be encouraged. Conclusion: Anakinra was associated with a reduction in CRP levels, indicating some anti-inflammatory effects but no effect on function, exercise capacity, and adverse effects.

show abstract

“…In the REDHART trial (the REcently Decompensated Heart failure Anakinra Response Trial), Anakinra, a recombinant human Il-1 receptor antagonist, improved peak aerobic exercise capacity after 12 weeks of treatment in patients with LVEF < 50% (from 14.5 mL/kg/minute to 16.1 mL/kg/minute; p = 0.009) ( Table 3 ) [ 36 ]. A currently underway single center, randomized, placebo-controlled, double-blind, phase II, randomized clinical trial is evaluating the 24-week effect of anakinra on cardiorespiratory capacity in patients with recent hospitalization for acute HFrEF decompensation [ 30 ].…”

Section: Evolving Therapeutic Targetsmentioning

confidence: 99%

Pharmacological Targets in Chronic Heart Failure with Reduced Ejection Fraction

Moloce

Costache

Nicolae

et al. 2022

Life

View full text Add to dashboard Cite

Heart failure management has been repeatedly reviewed over time. This strategy has resulted in improved quality of life, especially in patients with heart failure with reduced ejection fraction (HFrEF). It is for this reason that new mechanisms involved in the development and progression of heart failure, along with specific therapies, have been identified. This review focuses on the most recent guidelines of therapeutic interventions, trials that explore novel therapies, and also new molecules that could improve prognosis of different HFrEF phenotypes.

show abstract

Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study

Cited by 15 publications

References 42 publications

IL-1β is not critical to chronic heart dysfunction in mice with Chagas disease

IL-1β is not critical to chronic heart dysfunction in mice with Chagas disease

Anakinra in Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Pharmacological Targets in Chronic Heart Failure with Reduced Ejection Fraction

Contact Info

Product

Resources

About