CIRT Trial - Methotrexate Fails at Cardiovascular Prevention Save

Methotrexate has been shown to reduce cardiovascular (CV) deaths in rheumatoid arthritis (RA) patients. Given that inflammation underlies the pathogenesis of atherothrombosis, Dr. Paul Ridker and colleagues studied the value of low dose methotrexate (MTX) in preventing cardiovascular events.

The CIRT trial was prematurely halted in April 2018 as the Data Safety Monitoring Board judged that MTX was unable to  prevent CV events and that continuation would not likely favorably change these outcomes.

The study was published in the NEJM and presented at American Heart Association meeting in Chicago.

The large Cardiovascular Inflammation Reduction trial (CIRT) was funded by the NHLBI and halted based on a recommendation from the trial's Data and Safety Monitoring Board. This was a cardiovascular intervention trial and did not involve patients with RA or arthritis. 

This was a randomized, double-blind trial of low-dose MTX (escalated to 15 to 20 mg weekly) vs. placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease (stable atherosclerosis) who additionally had either type 2 diabetes or the metabolic syndrome. The primary endpoint was a composite of nonfatal myocardial infarction, nonfatal stroke, cardiovascular death or unstable angina that led to urgent revascularization.

After 2.3 years the trial was stopped. The primary endpoint occurred equally in those treated with MTX (n=201) or placebo (n=207) (hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). At the final visit, the mean MTX dose was roughly 19 mg/week but roughly 1 in 5 patients had permanently discontinued the trial regimen.

Compared with placebo, MTX treated patients had more liver enzyme elevations, leukopenia, higher MCV values, more  anemia and non–basal-cell skin cancers. MTX patients also had more oral ulcers and unintended weight loss. 

Additionally MTX did not significantly lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. 

These findings are surprising in light of the success of the CANTOS trial wherein canakinumab (an IL-1 inhibitor) significantly lowered CV events in high risk CV patients. 

One difference between trials is that the CANTOS trial enrolled patients with a prior myocardial infarction and elevated high sensitivity C-reactive protein (CRP) of 2.0 mg/L or more.  The mean entry CRP levels were lower in CIRT compared to CANTOS (~1.5 vs 4.5 mg/L) and statins were used by >85% of patients in both trials.  Yet, the CANTOS trial showed canakinumab to lower IL-1 and CRP levels while demonstrating significantly fewer CV events, CVA and cancer deaths.  Nevertheless, the FDA has denied Novartis application to use canakinumab in cardiac prevention by issuing a complete response letter (rejection).