Change in Eosinophil Count in Patients with Heart Failure Treated with Anakinra.

BACKGROUND: Interleukin-1 blockade with anakinra leads to a transient increase in eosinophil blood count (eosinophils) in patients with acute myocardial infarction. We aimed to investigate the effect of anakinra on changes in eosinophils in patients with heart failure (HF) and their correlation with cardiorespiratory fitness (CRF). METHODS: We measured eosinophils in 64 patients with HF (50% females), 55 (51-63) years of age, before and after treatment, and, in a subset of 41 patients, also after treatment cessation. We also evaluated CRF, measuring peak oxygen consumption (VO2) with a treadmill test. RESULTS: Treatment with anakinra significantly and transiently increased eosinophils, from 0.2 [0.1-0.3] to 0.3 [0.1-0.4] × 103 cells/µL (p < 0.001) and from 0.3 [0.2-0.5] to 0.2 [0.1-0.3] × 103 cells/µL, with suspension (p < 0.001). Changes in eosinophils correlated with the changes in peak VO2 (Spearman's Rho = +0.228, p = 0.020). Eosinophils were higher in patients with injection site reactions (ISR) (n = 8, 13%; 0.5 [0.4-0.6] vs. 0.2 [0.1-0.4] × 103 cells/µL, p = 0.023), who also showed a greater increase in peak VO2 (3.0 [0.9-4.3] vs. 0.3 [-0.6-1.8] mLO2·kg-1·min-1, p = 0.015). CONCLUSION: Patients with HF treated with anakinra experience a transient increase in eosinophils, which is associated with ISR and a greater improvement in peak VO2.

Patient Perceptions of Exertion and Dyspnea With Interleukin-1 Blockade in Patients With Recently Decompensated Systolic Heart Failure.

Interleukin-1 (IL-1) blockade is an anti-inflammatory treatment that may affect exercise capacity in heart failure (HF). We evaluated patient-reported perceptions of exertion and dyspnea at submaximal exercise during cardiopulmonary exercise testing (CPET) in a double-blind, placebo-controlled, randomized clinical trial of IL-1 blockade in patients with systolic HF (REDHART [Recently Decompensated Heart Failure Anakinra Response Trial]). Patients underwent maximal CPET at baseline, 2, 4, and 12 weeks and rated their perceived level of exertion (RPE, on a scale from 6 to 20) and dyspnea on exertion (DOE, on a scale from 0 to 10) every 3 minutes throughout exercise. Patients also answered 2 questionnaires to assess HF-related quality of life: the Duke Activity Status Index and the Minnesota Living with Heart Failure Questionnaire. From baseline to the 12-week follow-up, IL-1 blockade significantly reduced RPE and DOE at 3- and 6-minutes during CPET without changing values for heart rate, oxygen consumption, and cardiac workload at 3- and 6-minutes. Linear regression identified 6-minute RPE to be a strong independent predictor of both physical symptoms (Minnesota Living with Heart Failure Questionnaire; ß = 0.474, p = 0.002) and perceived exercise capacity (Duke Activity Status Index; ß = -0.443, p = 0.008). In conclusion, patient perceptions of exertion and dyspnea at submaximal exercise may be valuable surrogates for quality of life and markers of response to IL-1 blockade in patients with HF.

Meta-analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD.

The advent of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) ushered in a new era of dyslipidemia pharmacotherapy. The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran-a small interfering RNA-based agent targeting PCSK9-reported similar lipid-lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta-analysis (random-effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low-density lipoprotein cholesterol (LDL-C) was observed across all agents (-51% [95% confidence interval {CI}: -61%, -41%]). Despite the impressive reduction in LDL-C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73-0.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74-0.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26-3.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9-targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow-up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum.