Low-Dose Methotrexate Fails to Lower Risk of Heart Attack, Stroke

By Gene Emery

(Reuters Health) - Hoping to tap the anti-inflammatory powers of methotrexate, researchers have failed to show that a low-dose of the drug, already used to fight cancer and arthritis, can reduce the risk of heart attack or stroke.

The treatment, detailed Saturday at the American Heart Association Scientific Sessions meeting in Chicago and online in the New England Journal of Medicine, also failed to reduce levels of interleukin-1beta, interleukin-6 or C-reactive protein better than placebo in volunteers with stable atherosclerosis.

The trial, known as CIRT, was halted prematurely for futility after a median follow-up of 2.3 years.

A total of 4,786 volunteers received placebo or 15 to 20 mg of methotrexate weekly at 417 centers in North America.

The primary endpoint was a composite of cardiovascular death and nonfatal myocardial infarction or stroke. The research team also looked at hospitalization for unstable angina that results in an urgent revascularization.

That endpoint was reached at a rate of 4.13% per year in the methotrexate group and 4.31% in the placebo group.

But the treatment also led to more non-basal-cell skin cancers, lower hematocrit levels and leukocyte counts and higher liver enzyme levels.

Previous research has suggested that putting the brakes on inflammation can prevent atherosclerotic events. Methotrexate is already used to quell inflammation-related conditions such as rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, and people getting the drug for those conditions have reportedly had fewer heart attacks and strokes than expected.

In the CIRT study, 39% of the patients had multivessel coronary disease without a heart attack and 61% had been treated for myocardial infarction. In addition, all had type 2 diabetes or the metabolic syndrome. None had a history of chronic infection or problems that might be aggravated by methotrexate use. They were allowed into the trial only after a test period where they were able to take 15 mg of the drug once a week for at two weeks without side effects. All took 1 mg of folic acid daily. At the 6-month mark, methotrexate recipients had their dose increased to 20 mg per week.

When the trial was halted, 21% of methotrexate recipients and 22% getting placebo had stopped taking their pills.

The cancer rate was 72% higher among methotrexate recipients (P=0.02) with 52 cases in that group versus 30 with placebo. Drug recipients also had more mouth sores, oral pain, and unintended weight loss.

Results released last year showed that the anti-inflammatory monoclonal antibody canakinumab produced fewer cardiovascular events, so reducing inflammation may lower the odds of atherothrombosis, the researchers said. But "reducing the risk of cardiovascular events may depend on the pathway targeted."

SOURCE: https://bit.ly/2OCImQa

N Engl J Med 2018

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