Effect of age and sex on efficacy and tolerability of ß blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis.

OBJECTIVES: To determine the efficacy and tolerability of ß blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials. DESIGN: Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45. PARTICIPANTS: 13,833 patients from 11 trials; median age 64; 24% women. MAIN OUTCOME MEASURES: The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model. RESULTS: Compared with placebo, ß blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by ß blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give ß blockers, 15.6% in those receiving placebo). CONCLUSION: Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive ß blockers to reduce the risk of death and admission to hospital.Registration PROSPERO CRD42014010012; Clinicaltrials.gov NCT00832442.

Identification of a truncated IL-18R beta mRNA: a putative regulator of IL-18 expressed in rat brain.

Interleukin (IL)-18, a member of the IL-1 family, is a key mediator of peripheral inflammation and host defense responses, and has been implicated in inflammatory and neurodegenerative diseases in the brain. IL-18 acts via a receptor complex that closely resembles that of IL-1, consisting of a ligand binding protein, IL-18Ralpha, and an accessory protein, IL-18Rbeta. Here, we describe the presence of a splice variant of IL-18Rbeta that is predicted to encode a truncated soluble protein, consisting of only the first immunoglobulin-like domain of IL-18Rbeta (EMBL/Genbank accession number AJ550893). Both forms of IL-18Rbeta were expressed in rat cortex, striatum, hypothalamus, hippocampus, and also liver, and were detected in pure cultures of microglia, astrocytes and neurons. This novel splice variant is up-regulated rapidly in microglial cells by bacterial lipopolyssacharide (LPS). We propose that this putative truncated form of IL-18Rbeta is analogous to the soluble form of IL-1R accessory protein, and could act as an important regulator of IL-18 actions.