A placebo-controlled trial of methotrexate in more than 4,700 atherosclerosis patients did not reduce the incidence of cardiovascular events, dealing another blow to hopes that anti-inflammatory therapies can control heart disease.

Methotrexate is an anti-inflammatory that is used for the treatment of rheumatoid arthritis and other indications. The drug did not reduce the incidence of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death compared with placebo, show data from the failed CIRT trial, presented at the American Heart Association Scientific Sessions in November and published in the New England Journal of Medicine.

The negative results are a setback for a community that was re-invigorated in 2017 by the CANTOS trial of Novartis's anti-IL-1β therapy canakinumab. The anti-inflammatory antibody reduced the incidence of atherosclerotic events by 15%, showed the 10,000-patient trial. The benefit was greatest in patients who showed the largest reductions in IL-6 and CRP with treatment, buoying hopes that drugs that act on the IL-1–IL-6– CRP pathway could improve cardiovascular outcomes. Methotrexate is also thought to act on this pathway, prompting researchers to hope that the CIRT trial would validate the CANTOS findings. Instead, the CIRT investigators report that methotrexate did not reduce levels of IL-1, IL-6 or CRP.

CIRT investigators called these findings neutral, but informative. “The observations in CANTOS, CIRT and other trials highlight the importance of considering the mechanistic diversity of inflammatory pathways in atherosclerosis and of exploring approaches to their inhibition. Understanding these differences is likely to be crucial for future studies targeting inflammation in atherosclerosis,” they write in the New England Journal of Medicine.

Other anti-inflammatory agents that have failed to improve cardiovascular outcomes include GlaxoSmithKline's now-discontinued lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor darapladib. A large trial of colchicine, a nonspecific inhibitor of the NLRP3 inflammasome, is ongoing.

Separately, Novartis disclosed in October that the FDA has rejected a bid for a supplemental approval for canakinumab for cardiovascular risk reduction. The company is evaluating the regulatory complete response letter to decide on next steps for this drug.