When Anti‑Inflammatory Heart Drugs Don’t Work: What the Trials Tell Us

For decades researchers have debated whether inflammation is a cause of atherosclerosis or merely a marker of disease, and large clinical trials have produced evidence that is both illuminating and confounding. The 2017 CANTOS trial showed that canakinumab, an interleukin‑1β blocker, reduced major cardiovascular events among patients with prior myocardial infarction and elevated hsCRP, providing proof of principle that lowering specific inflammatory pathways can cut risk. Yet such success has not been uniform across agents or populations.

Subsequent studies have underscored this complexity. The CIRT trial found that low‑dose methotrexate, a broad anti‑inflammatory therapy, did not reduce cardiovascular events, and earlier pharmacologic approaches such as darapladib also failed in large outcome trials, suggesting that non-selective anti‑inflammatory strategies may not alter atherosclerosis. In July 2026 AstraZeneca and Ionis announced that eplontersen did not meet the primary endpoint in a Phase 3 trial for transthyretin‑mediated amyloid cardiomyopathy (ATTR‑CM), a distinct disease in which protein deposition, rather than classical atherosclerotic inflammation, drives pathology.

More targeted approaches remain under evaluation. Ziltivekimab, an antibody that inhibits the interleukin‑6 ligand, produced substantial reductions in hsCRP and thrombotic biomarkers in earlier studies, and the ZEUS cardiovascular outcomes trial is testing whether IL‑6 inhibition translates into fewer clinical events. If ZEUS and similar trials fail to show event reduction despite biomarker changes, investigators will need to reassess prevailing models, refine biomarker thresholds such as hsCRP and IL‑6, and identify which patients, if any, derive meaningful benefit. Consequently, while inflammation remains a plausible therapeutic target, current evidence demands precise hypotheses and careful trial design before clinicians alter practice.