Methotrexate unexpectedly disappoints in CV prevention
Low-dose methotrexate, which is approved for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders, has shown unexpectedly disappointing results in preventing cardiovascular (CV) events among patients with a prior myocardial infarction (MI) or multivessel coronary disease, according to CIRT*, potentially ruling out what could be an affordable option for treating inflammation related to atherosclerosis.
In the study, methotrexate 15–20 mg given weekly failed to prevent major adverse CV events vs placebo and did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein, which are known inflammatory markers. [N Engl J Med 2018;doi:10.1056/NEJMoa1809798]
These results were contrary to those of the CANTOS trial which showed that canakinumab, a human monoclonal antibody that targets the interleukin-1β innate immunity pathway, was able to reduce the risk of CV events when added to optimal medical therapy. [N Engl J Med 2017;377:1119-1131]
“CANTOS and CIRT were designed and ran in parallel … 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,” said study author Dr Paul Ridker of Brigham and Women’s Hospital in Boston, Massachusetts, US, who presented results of CIRT at AHA 2018. “So, we 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 RA.”
Unfortunately, there was no benefit observed with methotrexate in terms of reducing CV inflammation. Thus, research on the appropriate biological pathway for inflammation relevant to atherosclerotic events continues.
“Taken together, CIRT and CANTOS provide potentially helpful mechanistic observations about selective drug effects in targeting inflammation,” said discussant Prof Sidney Smith, Jr from the University of Carolina in Carolina, US. Two trials (LoDoCo and COLCOT) of colchicine, which also acts on IL-1β, should provide valuable information in this regard.”
CIRT stopped after 2.3 years for futility
Patients in the CIRT study also had type 2 diabetes or metabolic syndrome and were randomized to low-dose methotrexate or placebo. All received folate 1 mg daily to protect their liver. The trial was stopped by the Data and Safety Monitoring Board for futility after a median of 2.3 years. At that point 4,786 of the 6,158 eligible patients had completed the run-in phase and were randomized to treatment. The mean age of the patients was 66 years; 19 percent were women. The primary endpoint at the onset of the trial was a composite of nonfatal MI, nonfatal stroke, or CV death. Towards the conclusion of the trial in January 2018, but before the unblinding, hospitalization for unstable angina that led to urgent revascularization was added as a primary endpoint.
Methotrexate failed to reduce the risk of nonfatal MI, nonfatal stroke, or CV death (hazard ratio [HR], 1.01). There were significantly more adverse events (elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AS levels, mouth sores, oral pain) with methotrexate, with no difference in the risk of serious infection, gastrointestinal disorders, neurologic disorders, or haemorrhage between methotrexate and placebo. Methotrexate was also associated with a higher incidence of non–basal-cell skin cancers (p=0.002).
Experts are quite disappointed with the results. “Clearly, this is not going to be a therapy that moves forward for secondary prevention,” said Dr Donald Lloyd-Jones of Northwestern University and co-chair of the meeting. “This low-dose methotrexate has more broad-based anti-inflammatory effects … and we don’t necessarily understand how it works. We need more trials … we've got a lot more to learn.”