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CHICAGO -- Low-dose methotrexate given to reduce inflammation had no impact on cardiovascular events in high-risk but stable atherosclerosis, the CIRT randomized trial showed.

A weekly dose of 15 to 20 mg had no impact on the primary endpoint of major adverse cardiovascular events compared with placebo, Paul Ridker, MD, of Brigham and Women's Hospital in Boston, and colleagues reported here at the American Heart Association meeting and simultaneously online in the .

That was true for the original composite of nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular death (3.46 vs 3.43 per 100 person-years, HR 1.01, 95% CI 0.82-1.25) and for the final endpoint that was updated not long before the trial was stopped at 2.3 years, which added hospitalization for unstable angina leading to urgent revascularization (4.13 vs 4.31 per 100 person-years, HR 0.96, 95% CI 0.79-1.16).

Mortality actually came out numerically higher with low-dose methotrexate, both from cardiovascular causes (0.92 vs 0.80 per 100 person-years, HR 1.14, 95% CI 0.76-1.72) and overall (1.80 vs 1.55 per 100 person-years, HR 1.16, 95% CI 0.87-1.56).

"Clearly, this is not going to be a therapy that moves forward for secondary prevention," commented Donald Lloyd-Jones, MD, of Northwestern University and co-chair of the meeting.

The CANTOS trial had raised hopes by showing that canakinumab (Ilaris), a monoclonal antibody against interleukin-1 beta, reduced cardiovascular events by 15%. Although side effects, cost, and FDA rejection of a CV indication sidelined canakinumab for use in prevention, CANTOS was seen as proof of inflammation's role in atherothrombosis.

Low-dose methotrexate was chosen as a more broad-based anti-inflammatory agent, with a generic available, and a reputation as generally safe in wide use.

The findings were disappointing but not the end of the story, commented Hadley Wilson, MD, of Sanger Heart & Vascular Institute in Charlotte, North Carolina, "I do not think it closes the book on anti-inflammatories but it does say that we're going to have to be more specific with our anti-inflammatory agents, which are going to have to be more targeted to interleukin suppression ... It's not going to be an easy solution."

Notably, in CIRT, low-dose methotrexate didn't reduce levels of the inflammatory marker C-reactive protein or interleukin-1 beta or interleukin 6 in this stable atherosclerotic population as it has been shown to do in prior trials of rheumatoid arthritis and other systemic inflammatory conditions it is used to treat.

CIRT and CANTOS enrolled a similar patient population, other than that CANTOS targeted patients with residual inflammatory risk, and enrolled only those with persistently elevated high-sensitivity C-reactive protein levels. The median baseline C-reactive protein levels were 4.2 mg/L (about the 90th percentile of the normal distribution) vs 1.6 mg/L.

However, when asked at the session whether it was the CRP not being elevated enough in CIRT that drove the difference, Ridker said, “even among those who did have higher CRP levels, we saw no reduction in IL-1, IL-6,or CRP, so I suspect not. I think the most interesting observation is even on PCSK9 inhibitors — we’d driven the LDLs down to 20 — residual inflammatory risk based on CRP was still there.”

"This low-dose methotrexate has more broad-based anti-inflammatory effects," Lloyd-Jones noted. "We don't really necessarily understand how it works."

"I think we need more trials either specifically targeting molecules in the inflammatory pathway or where we get the LDL levels really low with something like a PCSK9 inhibitor, and then we find out if any of these anti-inflammatory drugs add any extra value when we're there," he continued. "We've got a lot more to learn before this is going to be prime-time therapy."

Targeting the interleukin-1 beta/interleukin-6 pathway with agents such as colchicine and oral NLRP3 inhibitors is being studied or in the works, Ridker and co-authors noted.

Their CIRT trial included 6,158 patients in the open-label run-in, among whom 4,786 were randomized to double-blind methotrexate or placebo. Dosing was adjusted by computerized algorithm based on levels of centrally measured laboratory values and adverse event reporting, with an initial dose of 15 mg and a target of 20 mg methotrexate. All participants got 1 mg of folate daily to help prevent liver side effects.

Eligibility required prior MI or multivessel coronary artery disease and either diabetes or the metabolic syndrome; exclusion criteria were at least as strict as those of the American College of Rheumatology for use of methotrexate in rheumatoid arthritis.

Adverse events more common with methotrexate than placebo included elevations in liver-enzyme levels, reduced white blood cell counts, and reduced hematocrit as well as mouth sores and oral pain. The incidence of non-basal-cell skin cancers was also higher with the drug (31 vs 10 cases, RR 3.08, P=0.002) -- "a finding that was unexpected and that merits further exploration," the researchers noted.

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