TABLE 2.
Other anti-inflammatory trials in HF.
| Trial acronym/registry number and Reference | Study design | Study population | Intervention | Drug mechanism of action | Follow-up | Outcomes |
| Gullestad et al., 2001a | Randomized, double-blind, placebo-controlled study | 40 II–III NYHA class ischemic and dilated cardiomyopathy HFrEF patients with LVEF of <40% (Norway) | Intravenous immunoglobulin therapy (IVIG) - induction therapy (1 daily infusion at 0.4 g/kg for 5 days) and thereafter as monthly infusions (0.4 g/kg) for a total of 5 months or placebo for a total period of 26 weeks (4 weeks after last IVIG or placebo infusion). | Immunomodulator (influences the concentration of cytokines and cytokine modulators; neutralizes microbial antigens and autoantibodies; Fc-receptor blockade; complement inactivation) | 6 months | - ↑ anti-inflammatory cytokine profile (IL-10, IL-1 receptor antagonist, and soluble tumor necrosis factor receptors) - improvement in clinical status - ↑ LVEF - ↓ N-terminal pro-atrial natriuretic peptide |
| Sliwa et al., 2002 | Prospective, randomized, double-blind, placebo-controlled study | 18 IV NYHA class dilated cardiomyopathy HFrEF patients (South Africa) with LVEF of <25% | 1-month therapy with pentoxifylline (400 mg 3 times daily) (n = 9) and placebo (n = 9) | Immunomodulator (phosphodiesterase inhibitor leading to ↑cAMP and downstream inhibition of proinflammatory mediators) | 1 month | - ↓ TNF-α levels and Fas/Apo-1 concentrations - improved symptoms and ↑ LVEF |
| Sliwa et al., 2004 | Single-center, prospective, double-blind, randomized, placebo-controlled | 38 II–III NYHA class ischemic HFrEF patients (South Africa) with LVEF of <35% | 2 parallel arms: pentoxifylline 400 mg TID (n = 20) or a matching placebo (n = 18) for 6 months in addition to standard therapy | Immunomodulator (phosphodiesterase inhibitor leading to ↑cAMP and downstream inhibition of proinflammatory mediators) | 6 months | - ↓ in plasma markers of inflammation, prognosis, and apoptosis. - improved symptoms and ↑ LVEF |
| Gullestad et al., 2005 | Double-blind, placebo-controlled study | 56 II–III NYHA class ischemic and dilated cardiomyopathy HFrEF patients (Norway) with LVEF of <40% | Thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks | Immunomodulator (alters the concentration of inflammatory cytokines; downregulates neutrophils) | 3 months | - ↓ total neutrophil count and ↑ TNF-α levels - ↓ heart rate - ↑ in LVEF and improvement in left ventricular remodeling with matrix-stabilizing net effect |
| Gong et al., 2006 | Prospective, randomized, placebo-controlled, single-blind study | 71 patients with CHF outpatients receiving conventional treatment (China) with LVEF of <35% | Intervention group (n = 35): Methotrexate 7.5 mg per week for 12 weeks Placebo group (n = 36) | Folate analog with anti-inflammatory properties: inhibits inflammatory cell proliferation; ↑ extracellular concentrations of adenosine (which exerts anti-inflammatory effects by binding to A2 receptors) | 12 weeks | - ↓ TNF-α, IL-6, MCP-1, sICAM-1, CRP - ↑ IL-10, soluble IL-1 receptor antagonist - Improved NYHA functional class, 6-min walk test distance and quality of life scores |
| GISSI-HF (Gruppo Italiano Per Lo Studio Della Sopravvivenza Nell’Insufficienza Cardiaca-Heart Failure) NCT00336336 (Tavazzi et al., 2008a) | Randomized, double-blind, placebo-controlled | NYHA functional class II–IV heart failure irrespective of cause and/or LVEF (Italy) with mean LVEF of <45% | Intervention: n-3 polyunsaturated fatty acids (n-3 PUFA) 1 g daily (n = 3494) vs. placebo (n = 3481) | Precursors of SPMs (which have proresolving and anti-inflammatory effects). Incorporation of n-3-PUFA on the membrane of target cells likely reduces electrical excitability (anti-arrhythmic effect). | 46.8 months | - ↓ in both all-cause mortality and the composite end point of all-cause mortality and hospitalization for cardiovascular causes in all the predefined subgroups, compared with the placebo group |
| METIS (METhotrexate Therapy on the Physical Capacity of Patients With ISchemic Heart Failure Trial) (Moreira et al., 2009) | Randomized double-blind, placebo-controlled trial | 50 patients with ischemic CHF (Brazil) with mean LVEF of <45% | Intervention group (n = 25): Methotrexate 7.5 mg per week plus folic acid (5 mg/week) for 12 weeks Placebo group (n = 25): Placebo plus folic acid (5 mg/week), for 12 weeks | Folate analog with anti-inflammatory properties: inhibits inflammatory cell proliferation; ↑ extracellular concentrations of adenosine (which exerts anti-inflammatory effects by binding to A2 receptors) | 12 weeks | - No effects on CRP - No effects on 6-min walk test distance - Trend toward improved NYHA scores |
| COPE-ADHF (Cardiac Outcome Prevention Effectiveness of Glucocorticoids in Acute Decompensated Heart Failure) (Liu et al., 2014) | Non-blinded randomized | 102 patients with ADHF (China) with mean LVEF of <45% | Intervention group: dexamethasone (20 mg/d) IV followed by prednisone (orally, daily, 1 mg/kg/d with a maximum dose of 60 mg/d) for 7 days and then tapered off in 3 days (n = 51); Control group (n = 51): standard care | Glucocorticoid receptor agonists that regulate the transcription of several genes involved in the inflammatory response. Also ↑ the expression of the receptor for natriuretic peptides (diuretic effect). | 30 days | - Safe therapy; - ↓ Serum creatinine - ↑ Diuresis, ↓weight - ↓ CV death at 30 days - Improved dyspnea and clinical status |
| Deftereos et al., 2014 | Single-center, prospective, double-blinded, placebo-controlled study | 267 Patients with stable CHF and systolic dysfunction (EF ≤ 40%) (Greece) with mean LVEF of <35% | Intervention group (n = 134): oral colchicine 0.5 mg twice daily (once daily if weight < 60 kg) for 6 months Placebo group (n = 133) | Microtubule inhibitor with anti-inflammatory properties: inhibits NLRP3 inflammasome activation; disruption of leukocyte functions. | 6 months | - Safe use of colchicine; - ↓ hsCRP, IL-6 - No effect on patient functional status, death or hospital stay |
| EXACT-HF study (Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients) (Givertz et al., 2015) | Multi-center, 1:1 randomized, double-blind, placebo-controlled | 253 II–IV NYHA class ischemic and dilated cardiomyopathy HFrEF patients (LVEF ≤ 40%) and elevated serum UA levels (≥9.5 mg/dL) (various centers in United States and Canada) | Allopurinol was given for 24 weeks starting with 300 mg by mouth once daily for 1 week, and if tolerated, increased to 600 mg daily. Patients unable to tolerate 600 mg were maintained on 300 mg. | Xanthine oxidase inhibitor; besides urate lowering, ↓ oxidative stress and inflammatory mediators. | 6 months | - Failed to improve clinical status, exercise capacity, quality of life, or LVEF at 24 weeks |
ADHF, acute decompensated heart failure; cAMP, cyclic Adenosine Monophosphate; CHF, chronic heart failure; CRP, C-reactive protein; CV, cardiovascular; HFrEF, heart failure with reduced ejection fraction; hsCRP, high sensitive C reactive protein; IL-6, interleukin 6; LVEF, left ventricular ejection fraction; MCP-1, Monocyte chemoattractant Protein-1; NLRP3, NOD-, LRR-and pyrin domain-containing protein 3; NYHA, New York Heart Association; PUFA, polyunsaturated fatty acids; QD, once a day; SPMs, specialized proresolving mediators; sICAM-1, soluble intercellular adhesion molecule-1; TID, three times daily; TNF-α, Tumor necrosis factor alpha.