Key result
Continuous log-transformed IL-6 was strongly associated with major cardiovascular events, with an inflammatory floor at IL-6 ≈ 1.8 pg/mL.
Why the study?
Residual inflammatory risk persists after ACS despite optimal lipid-lowering therapy, and the dose-response relationship between continuous IL-6 levels and MACE remained incompletely characterized.
What is the dose-response relationship between continuous high-sensitivity IL-6 levels and the risk of recurrent MACE in post-acute coronary syndrome patients?
Meta-Analysis (n=57,521)
What is the dose-response relationship between continuous high-sensitivity IL-6 levels and the risk of recurrent MACE in post-acute coronary syndrome patients?
Answers are grounded in this paper and cite their sources.
Identifies a non-linear inflammatory floor at IL-6 ≈ 1.8 pg/mL below which marginal MACE risk reduction becomes negligible, defining a potential therapeutic threshold for targeted IL-6 inhibition in post-ACS secondary prevention.
Background Residual inflammatory risk (RIR) persists in post-acute coronary syndrome (ACS) patients despite optimal lipid-lowering therapy. While interleukin-6 (IL-6) is a validated biomarker of cardiovascular inflammation, the dose-response relationship between continuous IL-6 levels and major adverse cardiovascular events (MACE) remains incompletely characterized. We hypothesized that a non-linear "inflammatory ceiling" exists, below which marginal risk reduction becomes negligible. Methods We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library from inception to March 2026 to identify relevant studies and conducted a dose-response meta-analysis of seven landmark trials encompassing 57,521 post-ACS patients. Restricted cubic spline (RCS) regression modeled the continuous association between log-transformed IL-6 and MACE hazard ratios. Pooled log(HR) per unit log(IL-6) was estimated using random-effects models. Publication bias was assessed via Egger's test. Results The pooled log(HR) per unit log(IL-6) was 0.300 (95% CI 0.216-0.384), confirming a strong log-linear association. RCS analysis revealed a critical "inflammatory floor" at IL-6 ≈ 1.8 pg/mL (HR = 1.49 vs reference), below which further reductions yielded minimal incremental benefit. In the CANTOS IL-6 substudy (n=4,833), on-treatment IL-6 below the median (1.65 pg/mL) conferred a 32% MACE reduction (HR 0.68, 95% CI 0.56-0.83), whereas levels above the median showed no benefit (HR 1.02, 95% CI 0.87-1.20). Anti-inflammatory therapies demonstrated consistent efficacy: CANTOS (IL-1β inhibition, HR 0.85, 95% CI 0.74-0.98), COLCOT (HR 0.77, 95% CI 0.61-0.96), and LoDoCo2 (HR 0.69, 95% CI 0.56-0.86). In CIRT, each unit increase in log(IL-6) conferred a 31% higher MACE risk (HR 1.31). CLEAR Outcomes demonstrated a nearly two-fold MACE risk in the highest hsCRP quartile (HR ≈ 1.97). Romeo et al. meta-analysis (n=13,604) confirmed that hsCRP ≥2 mg/L predicted 64% higher MACE risk (RR 1.64, 95% CI 1.33-2.03) Conclusion An inflammatory floor at IL-6 ≈ 1.8 pg/mL defines a therapeutic threshold for targeted IL-6 inhibitor therapy in post-ACS secondary prevention, optimizing patient selection and resource allocation.
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Purewal et al. (2026) conducted a meta-analysis in Post-acute coronary syndrome (ACS) (n=57,521). Continuous log-transformed high-sensitivity interleukin-6 (IL-6) levels and anti-inflammatory therapy vs. Reference IL-6 levels or on-treatment IL-6 above vs below median was evaluated on Major adverse cardiovascular events (MACE) (Pooled log(HR) 0.300 per unit log(IL-6), 95% CI 0.216-0.384). Continuous log-transformed IL-6 was strongly associated with major cardiovascular events, with an inflammatory floor at IL-6 ≈ 1.8 pg/mL.
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