Low-Dose Methotrexate for the Prevention of Atherosclerotic Events

Paul M Ridker, Brendan M Everett, Aruna Pradhan, Jean G MacFadyen, Daniel H Solomon, Elaine Zaharris, Virak Mam, Ahmed Hasan, Yves Rosenberg, Erin Iturriaga, Milan Gupta, Michelle Tsigoulis, Subodh Verma, Michael Clearfield, Peter Libby, Samuel Z Goldhaber, Roger Seagle, Cyril Ofori, Mohammad Saklayen, Samuel Butman, Narendra Singh, Michel Le May, Olivier Bertrand, James Johnston, Nina P Paynter, Robert J Glynn, CIRT Investigators

Abstract

Background: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit.

Methods: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point.

Results: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo.

Conclusions: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

Copyright © 2018 Massachusetts Medical Society.

Figures

Figure 1. Laboratory Findings.
Figure 1. Laboratory Findings.
Shown are the effects of low-dose methotrexate (LDM) and placebo on hepatic enzyme levels (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), hematologic measures (mean corpuscular volume, white-cell count, hematocrit level, and hemoglobin level), inflammatory mediators (interleukin-1β, interleukin-6, and high-sensitivity Creactive protein [CRP] levels), and lipid levels (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides). Data shown are the changes from enrollment to 8 months after randomization. The horizontal line in each box represents the median, the top and bottom of the boxes the interquartile range, and the whiskers 1.5 times the interquartile range.
Figure 2. Cumulative Incidence of the Final…
Figure 2. Cumulative Incidence of the Final Primary End Point and the Original Primary End Point.
Shown is the cumulative incidence of the final primary end point of major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) or hospitalization for unstable angina that led to urgent revascularization (Panel A) and the cumulative incidence of the original primary end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death (Panel B). The inset in each panel shows the same data on an enlarged y axis.

Source: PubMed

3
Předplatit