TABLE 1.
Trials targeting major inflammatory mediators of HF.
| Target | Trial acronym/registry number and Reference | Study design | Study population | Intervention | Drug mechanism of action | Follow-up | Outcomes |
| TNF-α | Deswal et al., 1999 | Randomized double-blind | 18 HFrEF patients with NYHA class III (United States) with LVEF of <35% | Intervention groups: single intravenous infusion of 1, 4, or 10 mg/m2 of etanercept over 30 min (n = 4 for each dose) Placebo group (n = 6) | TNF-α inhibitor (dimeric recombinant protein fusing the TNF receptor 2 to the Fc region of the human IgG1 antibody) | 14 days | - No adverse effects - 4 or 10 mg/m2 of etanercept: ↓ TNF-α, IL 6 ↑ quality of life, 6-min walk test distance and ejection fraction |
| Bozkurt et al., 2001 | Randomized, double-blind, placebo-controlled | 47 HFrEF patients with NYHA class III to IV (United States) with LVEF of <30% | Intervention groups: subcutaneous injections of etanercept 5 mg/m2 (n = 16) or 12 mg/m2 (n = 15) 2x/week for 3 months Placebo group (n = 16) | TNF-α inhibitor (dimeric recombinant protein fusing the TNF receptor 2 to the Fc region of the human IgG1 antibody) | 3 months | - Safe treatment; - Dose-dependent improvement in LV structure, remodeling and function | |
| Fichtlscherer et al., 2001 | Randomized | 18 patients with CHF (Germany) with LVEF of <30% | Intervention group (n = 13): single dose of subcutaneous injection of 25 mg etanercept Control group (n = 5) | TNF-α inhibitor (dimeric recombinant protein fusing the TNF receptor 2 to the Fc region of the human IgG1 antibody) | 7 days | - Improved systemic endothelial vasodilator capacity; - Positive correlation between the increase in ACh-induced-forearm blood flow responses and baseline TNF-α serum values | |
| ATTACH (Anti-TNF Therapy Against Congestive Heart Failure Trial) (Chung et al., 2003) | Randomized double-blind | 150 HFrEF patients with stable NYHA class III or IV (United States) with LVEF of ≤35% | Intervention groups: 2-h intravenous infusion of infliximab 5 mg/kg (n = 50), infliximab 10 mg/kg (n = 51) at 0, 2 and 6 weeks Placebo group (n = 49) | TNF-α inhibitor (Anti-TNF-α, mouse-human chimeric monoclonal antibody) | 28 weeks | - No improvement in clinical status - 10 mg/kg infliximab: ↑ risk of death or hospitalization - 5 mg/kg infliximab: ↓ CRP, IL-6; ↑ EF (modestly) | |
| RENEWAL (Randomized Etanercept Worldwide Evaluation): combined data of RENAISSANCE and RECOVER trials in a pre-specified study (Mann et al., 2004) | Randomized double-blind, placebo-controlled | 1673 patients with CHF (United Kingdom, Sweden, Germany, Holland, Denmark, Italy, France, Norway, Israel, Australia, New Zealand, United States) with LVEF of <30% | Intervention groups: etanercept subcutaneous injection 25 mg 3x weekly (n = 308), 25 mg 2x weekly (n = 683) Placebo group (n = 682) | TNF-α inhibitor (dimeric recombinant protein fusing the TNF receptor 2 to the Fc region of the human IgG1 antibody) | 24 weeks | - No effects on the rate of death or hospitalization | |
| IL-1 | D-HART (Diastolic Heart failure Anakinra Response Trial) NCT01542502 (Van Tassell et al., 2014) | Randomized, double blind, placebo-controlled, crossover pilot study | 12 patients with HFpEF (United States) | SC injection of 100 mg of anakinra daily for 14 days and an additional 14 days of placebo or SC injection of placebo daily for 14 days and 100 mg of anakinra for an additional 14 days | Inhibits IL-1 binding to the IL-1 type I receptor (recombinant, non-glycosylated form of the endogenous IL-1 receptor antagonist peptide) | 28 days | - ↓ systemic inflammatory response - ↑ aerobic exercise capacity of patients with HFpEF and elevated plasma CRP levels |
| NCT01936844 (Van Tassell et al., 2016) | Randomized double-blinded placebo-controlled pilot study | 30 patients with ADHF (United States) with LVEF of <40% | 100 mg anakinra twice daily for 3 days followed by once daily for 11 days or matching placebo | Inhibits IL-1 binding to the IL-1 type I receptor (recombinant, non-glycosylated form of the endogenous IL-1 receptor antagonist peptide) | 14 days | - ↓ systemic inflammatory response in patients with ADHF | |
| CANTOS (Canakinumab anti-Inflammatory Thrombosis Outcome Study) NCT01327846 (Ridker et al., 2017) | Randomized, double-blind trial | 10,061 patients with previous MI and hsCRP ≥ 2 mg/L (North America, South America, Europe, Asia, Africa, Australia) | 3 doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) | IL-1β inhibitor (monoclonal antibody which binds to human IL-1β, blocking its interaction with IL-1 receptors) | 48 months | - ↓ rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering - ↑ incidence of fatal infection than placebo | |
| REDHART (Recently Decompensated Heart Failure Anakinra Response Trial) NCT01936909 (Van Tassell et al., 2017) | Randomized in one of 3 treatment duration arms | 60 patients with recently decompensated systolic HF (United States) with LVEF of <50% | 1:1:1 ratio to 1 daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo | Inhibits IL-1 binding to the IL-1 type I receptor (recombinant, non-glycosylated form of the endogenous IL-1 receptor antagonist peptide) | 24 weeks | - ↓serum CRP values - ↑ peak VO2 in the group receiving anakinra for 12 weeks. | |
| D-HART2 (Diastolic Heart Failure Anakinra Response Trial 2) NCT02173548 (Van Tassell et al., 2018) | 2:1 phase 2, randomized, double-blind, placebo-controlled | 31 patients with HFpEF (Sweden) | IL-1 blockade with anakinra: 100 mg subcutaneously daily (n = 21) or placebo (n = 10) for 12 weeks | Inhibits IL-1 binding to the IL-1 type I receptor (recombinant, non-glycosylated form of the endogenous IL-1 receptor antagonist peptide) | 24 weeks | - ↓ serum hsCRP values - ↓ serum NT-pro-BNP | |
| IL-6 | Kobayashi et al., 2014 | Pilot study | 20 women with rheumatoid arthritis (RA) without cardiac symptoms (Japan) | Tocilizumab (TCZ; 8 mg/kg IV every 4 weeks) prescribed for patients with RA with an inadequate clinical response to methotrexate | IL-6 inhibitor (anti-IL-6 receptor monoclonal antibody which binds to soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling) | 52 weeks | - ↑increased EF - ↓LVMI associated with disease activity - regression of LV eccentric hypertrophy |
| NCT01491074 (Kleveland et al., 2016) | Two-center double-blind, randomized, placebo-controlled phase 2 trial | 117 patients with non-ST-elevation myocardial infarction (Norway) | Single dose (intravenous infusion) of the anti-IL-6R antibody tocilizumab 280 mg or matching placebo | IL-6 inhibitor (anti-IL-6 receptor monoclonal antibody which binds to soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling) | 3 and 6 months | - ↓ inflammatory response and primarily PCI-related TnT release in NSTEMI patients | |
| Yokoe et al., 2018 | 70 patients with RA free of cardiovascular disease | Tocilizumab prescribed for patients with active RA - 8 mg/kg of intravenous TCZ every 4 weeks during 24 weeks | IL-6 inhibitor (anti-IL-6 receptor monoclonal antibody which binds to soluble and membrane-bound IL-6 receptors, inhibiting IL-6 signaling) | 24 weeks | - ↓ NT-pro-BNP levels | ||
| RESCUE (Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition) NCT03926117 (Ridker et al., 2021) | Randomized, double-blind, phase 2 trial (at 40 clinical sites) | 264 participants with moderate-to-severe CKD and hsCRP ≥ 2 mg/L (high CV risk) (United States) | 66 were randomly assigned to each of the four treatment groups (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7.5, 15, or 30 mg every 4 weeks | IL-6 inhibitor (monoclonal antibody directed against the IL-6 ligand) | 24 weeks | - ↓hsCRP values - Ziltivekimab was well tolerated | |
| MPO | Hemodynamic Effects of a Novel Myeloperoxidase Inhibitor With Exercise in Heart Failure With Preserved Ejection Fraction - A Randomized, Double-Blind, Placebo Controlled Proof of Principle Study NCT03611153 | Randomized, double-blind, placebo controlled proof of principle study | 30 HFpEF patients referred to the catheterization laboratory for evaluation of breathlessness or shortness of breath | A single administration dose of 30 mg oral MPO inhibitor (AZD4831) or placebo given orally following baseline, resting and exercise testing in patients during right heart catheterization. | Potent and selective MPO inhibitor | 9–14 days after the study drug dosage | Ongoing study |
| CRP | CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) (Kjekshus et al., 2007) | Single-blind, randomized, placebo controlled | 5,011 II–IV NYHA class ischemic HFrEF patients (371 sites in 19 European countries, Russia, and South Africa) with LVEF of <35% | Intervention group (n = 2514): rosuvastatin 10 mg daily treatment for at least 3 months or placebo (n = 2497) | HMG-CoA reductase inhibitor with pleiotropic actions (e.g., antioxidant, anti-inflammatory, improvement of endothelial function) | 32.8 months | - ↓ CRP values if CRP > 2.0 mg/L - ↓ hospitalizations for HF - No effect on the composite of cardiovascular-related death, non-fatal MI or stroke; |
| GISSI-HF (Gruppo Italiano Per Lo Studio Della Sopravvivenza Nell’Insufficienza Cardiaca-Heart Failure) NCT00336336 (Tavazzi et al., 2008b) | Randomized, double-blind, placebo-controlled | 4,574 II–IV NYHA class ischemic and dilated cardiomyopathy HFrEF patients (Italy) with mean LVEF of <45% | Intervention group (n = 2285): rosuvastatin 10 mg daily treatment for at least 3 months or placebo (n = 2289) | HMG-CoA reductase inhibitor with pleiotropic actions (e.g., antioxidant, anti-inflammatory, improvement of endothelial function) | 46.8 months | - ↓ hsCRP values at 3 months - No effect on all-cause death or composite of all-cause death or hospitalization for cardiovascular causes | |
| NOS | Cotter et al., 2000 | Single-center, preliminary report | 11 patients with extensive MI complicated with CS (Israel) | L-NMMA - 1 mg/kg bolus and 1 mg/kg/h continuous IV drip for 5 h. | Non-selective NOS inhibitor | 1–3 months | - No adverse effects - ↑ BP - ↑ Urinary output |
| LINCS (L-NAME (a NO synthase inhibitor) In the treatment of refractory Cardiogenic Shock) (Cotter et al., 2003) | Single-center, prospective randomized study | 30 patients with refractory CS (Israel) | Intervention group (n = 15): supportive care in addition to L-NAME - 1 mg/kg bolus and 1 mg/kg/h continuous IV drip for 5 h; Control group (n = 15): supportive care alone | Non-selective NOS inhibitor | 4 months | - ↑ BP - ↑ Urinary output - ↓ Time of mechanical ventilation - ↓ Time of intra aortic ballon pump support | |
| SHOCK-2 (Should we inhibit nitric Oxide synthase in Cardiogenic Shock 2) (Dzavík et al., 2007) | Multicenter phase II, randomized, placebo-controlled, dose ranging study | 79 patients with acute MI complicated by persistent CS despite PCI (United States, Canada, Germany, Israel, Austria, Denmark) | Intervention groups (n = 15/15/15/14): L-NMMA - 0.15/0.5/1.0/1.5 mg/kg IV bolus and 0.15/0.5/1.0/1.5 mg/kg/h infusion for 5 h; Placebo group (n = 20): 0.9% normal saline IV bolus, and 5 h infusion. | Non-selective NOS inhibitor | 2 h after study initiation (MAP outcome) or 30 days (mortality outcome) | - No adverse effects - ↑ BP at 15 min (modestly) - No effect on BP at 2 h - No effects on glucose and urinary output - No significant differences on mortality at 30 days | |
| TRIUMPH (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock) (TRIUMPH Investigators et al., 2007) | International multicenter, randomized, double blind placebo-controlled | 398 patients with refractory CS complicating MI despite PCI (eight countries in North America and Europe) | Intervention group (n = 206): Tilarginine (L-NMMA) - 1 mg/kg bolus and 1 mg/kg/h infusion for 5 h; Placebo group (n = 190). | Non-selective NOS inhibitor | 6 months | - No effect on 30-day all-cause mortality - ↑ SBP at 2 h - No effect on the resolution of shock, on reinfarction, or on renal function. |
ACh, acetylcholine; ADHF, acute decompensated heart failure; BP, blood pressure; CHF, chronic heart failure; CKD, chronic kidney disease; CRF, cardiorespiratory fitness; CRP, C-reactive protein; CS, cardiogenic shock; CV, cardiovascular; EF, ejection fraction; HF, heart failure; HFpEF, Heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HMG-CoA, β-hydroxy β-methylglutaryl Coenzime A; hsCRP, high sensitive C reactive protein; IL-1, interleukin 1; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; L-NAME, N-Nitro-L-Arginine-Methyl Ester; L-NMMA, N-monomethyl L-arginine; LV, left ventricular; LVMI, left ventricular mass index; MI, myocardial infarction; MPO, myeloperoxidase; NOS, nitric oxide synthase; NSTEMI, non-ST segment elevation myocardial infarction; NT-pro-BNP, N-terminal-pro-B-type Natriuretic Peptide; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; RA, rheumatoid arthritis; SBP, systolic blood pressure; SC, subcutaneous; sICAM-1, soluble intercellular adhesion molecule-1; TCZ, tocilizumab; TNF-α, tumor necrosis factor alpha; TnT, troponin T; VO2, volume of oxygen consumption.