Low-Dose Methotrexate for the Prevention of Atherosclerotic Events

Paul RidkerDirector, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital

“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. 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.”

Paul RidkerDirector, Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital

“Back then, we were hoping to have two swings of the bat. With one, a very narrow spectrum targeted anti-inflammatory—that was obviously CANTOS—but we didn't know 8 or 9 years ago if our hunch about the biology was correct or not. So we also wanted to have a second swing of the bat using a generic, inexpensive, broad-spectrum anti-inflammatory that's well known to be clinically effective, at least for rheumatoid arthritis.”

“The CIRT trial showed that low-dose methotrexate didn't reduce atherosclerotic events, but it also didn't reduce markers of inflammation, so it neither confirms nor refutes the inflammatory hypothesis of atherosclerosis. The authors note that a significant difference between CIRT and CANTOS was that CANTOS, by design, included patients with higher baseline inflammatory risk as evidenced by a persistently elevated high-sensitivity C-reactive protein level (median, 4.2 mg/L in CANTOS vs. 1.6 mg/L in CIRT). The main takeaway is that anti-inflammatory therapy may not have an impact if there isn't a lot of inflammation at baseline or if the agent chosen doesn't actually decrease inflammation.”