Low-Dose Methotrexate for the Prevention of Atherosclerotic Events

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, .)

The Potential of Probiotics in the Prevention and Treatment of Atherosclerosis

“…For example, one potential anti‐inflammatory that is currently used in the treatment of rheumatoid arthritis is methotrexate . However, the CIRT (Cardiovascular Inflammation Reduction Trial) trial of low‐dose methotrexate failed to reduce the incidence of cardiovascular events in patients with hyperglycemia and high levels of CRP . Additionally, the highly anticipated lipoprotein‐associated phospholipase A2 inhibitor darapladib failed to reduce cardiovascular risk in two separate clinical trials; STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) and SOLID‐TIMI 52 (The Stabilisation Of pLaques usIng Darapladib‐Thrombolysis In Myocardial Infarction 52) .…”

When Randomized Clinical Trials and Real‐World Evidence Say the Same: Tocilizumab and Its Cardiovascular Safety

“…In other circumstances, apparent discrepancies between RCTs and RWE studies may be attributable to different patient populations or different measurement approaches, making a direct comparison less meaningful. Several RWE studies of RA patients have suggested potential CV benefits from treatment with methotrexate , which were discordant with the findings from the Cardiovascular Inflammation Reduction Trial (CIRT), which found no CV benefits from methotrexate . However, CIRT did not include any patients with RA or patients with any other systemic inflammatory diseases, resulting in a study population of patients with minimal systemic inflammation and a median C‐reactive protein level of 1.5 mg/liter.…”

Atherosclerosis: Beyond the lipid storage hypothesis. The role of autoimmunity

“…68 Vaccination with ox-LDL as a therapeutic strategy for atherosclerosis remains an elusive approach in humans 7 while a clinical trial of intravenous immunoglobulin, which contains natural anti-ox-LDL antibodies, seems to exert anti-atherogenic role. 70 Similarly, TNF blockade seems to confer protection against atherosclerosis in RA patients. 60 Additionally, methotrexate treatment seems to reduce and CV events in patients with underlying rheumatic diseases such as rheumatoid arthritis (RA) and psoriasis, but not in those with coronary disease and concomitant type 2 Diabetes Mellitus (DM) or metabolic Syndrome.…”