Low-dose methotrexate fails to reduce cardiovascular events

Results of the CIRT trial presented at the American Heart Association Scientific Sessions dimmed hopes that low-dose methotrexate can reduce cardiovascular events but furthered researchers’ understanding of which inflammation-targeting therapies might succeed in that regard.

The Cardiovascular Inflammation Reduction Trial (CIRT) included 4,786 patients with previous myocardial infarction or multivessel coronary disease who also had either type 2 diabetes or metabolic syndrome. Patients were randomized to receive 15 to 20 mg weekly of methotrexate or a matching placebo, and all of them took 1 mg of folate each day.

After a median follow-up of 2.3 years, patients treated with methotrexate—commonly used for inflammatory conditions including rheumatoid arthritis—showed no significant reduction in a composite of cardiovascular outcomes including nonfatal MI, stroke, cardiovascular death or hospitalization for angina requiring urgent revascularization. Event rates occurred in 4.13 participants per 100 person-years in the treated group and 4.31 in the placebo group, a statistically insignificant 4 percent relative reduction.

Also, methotrexate wasn’t found to reduce interleukin-1β, interleukin-6 or C-reactive protein (CRP) levels compared to placebo, and was linked to higher liver-enzyme levels, reductions in leukocytes and hematocrit and more cases of non-basal-cell skin cancers.

The negative trial results are important to weigh against the CANTOS trial, which found another high-risk population with stable atherosclerosis derived cardiovascular benefit from canakinumab.

“The results from CIRT and CANTOS, when considered together, tell us something critically important: Not all inflammation is the same, and not all drugs that target inflammation are the same,” Paul Ridker, MD, lead author of both studies and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, said in a press release.

“While it is disappointing that an inexpensive drug like methotrexate did not have the effects we previously saw in CANTOS, the results from CIRT shed crucial light on the underlying biology that connects inflammation with cardiovascular disease. The divergent trial results provide a clear roadmap to guide our efforts going forward.”

Notably, CANTOS participants had persistently elevated CRP levels, whereas those levels were considered within the normal range among CIRT patients. Another key difference is canakinumab specifically inhibits the pro-inflammatory pathway connecting interleukin-1β to interleukin-6. Methotrexate, on the other hand, is believed to have anti-inflammatory effects through other means, Ridker and colleagues noted in the New England Journal of Medicine.

“Although abundant data indicate that inflammation contributes critically to atherothrombosis, an important provisional hypothesis deriving from these two contemporary trials is that reducing the risk of cardiovascular events may depend on the pathway targeted,” they wrote. “Understanding these differences is likely to be crucial for future studies targeting inflammation in atherosclerosis.”