American Heart Association

American Heart Association

Issue: December 2018
Perspective from Steven E. Nissen, MD, MACC
November 11, 2018
4 min read

CIRT: Methotrexate Fails to Prevent Atherosclerotic Events

Issue: December 2018
Perspective from Steven E. Nissen, MD, MACC
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Paul M. Ridker

CHICAGO — Treatment with low-dose methotrexate did not reduce risk for CV events compared with placebo and conferred elevated risk for nonbasal-cell skin cancers, according to results of the CIRT trial.

Like the CANTOS trial, CIRT was designed to test the inflammation hypothesis for CVD prevention, Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, said during a press conference at the American Heart Association Scientific Sessions. Unlike CANTOS, however, the CIRT patient population did not have elevated levels of high-sensitivity C-reactive protein (1.6 mg/L vs. 4.2 mg/L in CANTOS), and the results did not indicate that an anti-inflammatory therapy reduced CVD risk.

“These were lower-risk-group patients [than in CANTOS] based on inflammatory markers,” Sidney C. Smith Jr., MD, FAHA, FESC, FACP, MACC, professor of medicine at the University of North Carolina-Chapel Hill, past president of the AHA and the World Heart Federation, said during a discussion of the CIRT data. “In addition, the LDL was reduced in CIRT to 68 mg/dL, whereas the group in CANTOS had a mean of 82 mg/dL. The group in CANTOS is arguably at higher risk.”

‘A neutral, but very informative study’

The agent tested in CANTOS, canakinumab (Novartis), reduced inflammation through the interleukin-1 beta/interleukin-6/CRP pathway. The agent tested in CIRT — methotrexate — is used to treat rheumatoid arthritis and psoriatic arthritis, and works through a different mechanism, so it did not have any effect on levels of IL-1 beta, IL-6 or CRP, Ridker said.

“The interesting thing to us, as investigators, is that between these two trials, we learned an important piece of biology,” Ridker said during the press conference. “The inflammation hypothesis has been proven and seems to require inhibition of the IL-1B/IL-6/CRP pathway. In that sense, this is a neutral but very informative study.”

Sidney C. Smith Jr.

CIRT enrolled 4,786 patients (mean age, 66 years; 19% women) with prior MI or multivessel CAD and diabetes or metabolic syndrome on background therapy of folate 1 mg per day. Patients were randomly assigned to low-dose methotrexate (weekly dose, 15 mg to 20 mg) or placebo.

Treatment with low-dose methotrexate did not reduce risk for CV events compared with placebo and conferred elevated risk for nonbasal-cell skin cancers, according to results of the CIRT trial.
Source: Adobe Stock

The primary endpoint at the start of the trial was CV death, nonfatal MI or nonfatal stroke. Near the end of the trial, but before unblinding, hospitalization for unstable angina leading to urgent revascularization was added to the composite primary endpoint.


CIRT was stopped for futility after a median of 2.3 years of follow-up, Ridker said.

The final primary endpoint was similar between the groups: 4.13 per 100 person-years with methotrexate vs. 4.31 per 100 person-years with placebo (HR = 0.96; 95% CI, 0.79-1.16), according to data presented.

The rate of the original primary endpoint, excluding hospitalization for unstable angina, also did not differ: 3.46 per 100 person-years with methotrexate vs. 3.43 per 100 person-years with placebo (HR = 1.01; 95% CI, 0.81-1.25).

There were no differences between the groups in the secondary and tertiary endpoints of all-cause mortality, HF hospitalization, major adverse CV events/revascularization, MI, stroke, CV death, urgent coronary revascularization or any coronary revascularization.

Thirty-one patients in the methotrexate group developed nonbasal-cell skin cancer compared with 10 in the placebo group (rate ratio = 3.08; P = .002). According to Ridker, this finding drove the significant difference in overall cancer (52 vs. 30; rate ratio = 1.72; P = .02).

In context

“Taken together, the CANTOS and CIRT trials indicate that inflammation inhibition can reduce cardiovascular event rates independent of lipid-lowering and blood pressure mechanisms,” Ridker said here. “However, the IL-1B/IL-6/CRP pathway appears to be important for this process. Hopefully these trials will point us in a direction where we know to look at how to act upon this process.”

The results were simultaneously published in The New England Journal of Medicine. – by Erik Swain


Ridker PM, et al. LBS.02 – Late Breaking Clinical Trial: Novel Approaches to CV Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Ridker PM, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809798.

Disclosures: The study was funded by the NHLBI. Ridker reports he received research grants from Kowa, the NHLBI, Novartis and Pfizer; received personal fees from CiviBio, Corvidia, Inflazome, Novartis and Pfizer; and is listed as a co-inventor on patents of three products licensed to AstraZeneca and Siemens.