Evidence map›Paper›PMID 30415610›Full record

Trial reportThe New England journal of medicine2019

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 and 17 more

3 registry-linked trialsOpen access · bronzeAbstract readMulticenter StudyRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in The New England journal of medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 677 papers, 6 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
677citing papers in PubMed, 6 pooled it
125.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01594333 phase3completednot on this map

A Randomized, Double-blind, Placebo-controlled, Event-driven Trial of Weekly Low-dose Methotrexate (LDM) in the Prevention of Cardiovascular Events Among Stable Coronary Artery Disease Patients With Type 2 Diabetes or Metabolic Syndrome

TypeinterventionalSponsorBrigham and Women's HospitalRan2013 to 2019Enrolled4,786ConditionsCardiovascular DiseaseArmsMethotrexate, Placebo
NCT04616872 phase2 / phase3unknown statusnot on this mapstarted 2020, after this paper: background citation

Treatment of Patients With Coronary and Aortic Atherosclerotic Disease With Methotrexate-associated to LDL Like Nanoparticles. A Randomized, Double-blind, Placebo-control Trial

TypeinterventionalSponsorUniversity of Sao Paulo General HospitalRan2020 to 2023Enrolled40ConditionsAtherosclerosis, Coronary Artery Disease, InflammationArmsMethotrexate-LDE, Placebo-LDE
NCT05956145 nacompletednot on this mapstarted 2021, after this paper: background citation

Effect of Low Dose of Colchicine on Platelet Reactivty in Patients With Chronic Coronary Disease

TypeinterventionalSponsorUniversity of Sao PauloRan2021 to 2024Enrolled80ConditionsPlatelet Aggregation, Spontaneous, Coronary Artery DiseaseArmsColchicine 0.5 MG, Placebo
3 · Its place in the literature

Who cites it

677 citing papers in PubMed, 6 syntheses or guidelines pooled it, 1,264 citations in OpenAlex.

  1. Pooled it
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  3. Review of OxLDL Driven Inflammatory Cell Activation.Current atherosclerosis reports · 2025
    Pooled it
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  5. Pooled it
  6. Guideline
  7. Trial
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  9. Trial
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  17. [EJNMMI research · 2026
    Review
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617 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors at 7 institutions in 3 countries.

Paul M RidkerFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Brendan M EverettFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).ORCID 0000-0002-6331-5224
Aruna PradhanFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Jean G MacFadyenFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Daniel H SolomonFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Elaine ZaharrisFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Virak MamFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Ahmed HasanFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Yves RosenbergFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Erin IturriagaFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Milan GuptaFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Michelle TsigoulisFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Subodh VermaFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Michael ClearfieldFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Peter LibbyFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Samuel Z GoldhaberFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Roger SeagleFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Cyril OforiFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Mohammad SaklayenFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Samuel ButmanFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Narendra SinghFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Michel Le MayFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Olivier BertrandFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
James JohnstonFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Nina P PaynterFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
Robert J GlynnFrom the Center for Cardiovascular Disease Prevention, Division of Preventive Medicine (P.M.R., B.M.E., A.P., J.G.M., E.Z., V.M., N.P.P., R.J.G.), and the Divisions of Cardiovascular Medicine (P.M.R., B.M.E., P.L., S.Z.G.) and Rheumatology (D.H.S.), Brigham and Women's Hospital, Boston; the National Heart, Lung, and Blood Institute, Bethesda, MD (A.H., Y.R., E.I.); McMaster University, Hamilton (M.G.), the Canadian Collaborative Research Network, Brampton (M.T.), St. Michael's Hospital, Toronto (S.V.), the University of Ottawa Heart Institute, Ottawa (M.L.M.), and KMH Cardiology, Diagnostic and Research Centres, Mississauga (J.J.), ON, and Laval University, Quebec City, QB (O.B.) - all in Canada; Touro University, Vallejo, CA (M.C.); Cardiology Associates Carolina, Morganton, NC (R.S.); Wooster Community Hospital, Wooster (C.O.), and Dayton Veteran Affairs Medical Center, Dayton (M.S.) - both in Ohio; Verde Valley Medical Center, Cottonwood, AZ (S.B.); and Atlanta Heart Specialists, Atlanta (N.S.).
CIRT Investigators
National Heart Lung and Blood Institute · USBrigham and Women's Hospital · USCanadian Respiratory Research Network · CACotton (United States) · USSt Michael’s Hospital · IETouro University California · USUniversity of Ottawa · CA

Funding

Cardiovascular Inflammation Reduction Trial (CIRT)U01HL101422 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI RIDKER, PAUL M. · 2011 to 2018
$55.4M
Cardiovascular Inflammation Reduction Trial (CIRT): DCCU01HL101389 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GLYNN, ROBERT J · 2011 to 2016
$6.6M
NHLBI NIH HHS U01 HL101389NHLBI NIH HHS U01 HL101422
6 · The paper itself

Abstract

backgroundInflammation 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.

methodsWe 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.

resultsThe 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.

conclusionsAmong 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.).

Indexed as

AgedAtherosclerosisCardiovascular DiseasesConfidence IntervalsCoronary Artery DiseaseC-Reactive ProteinDiabetes Mellitus, Type 2Double-Blind MethodFemaleFollow-Up StudiesHumansImmunosuppressive AgentsInterleukin-1betaInterleukin-6MaleMetabolic SyndromeC-Reactive ProteinImmunosuppressive AgentsInterleukin-1betaInterleukin-6MethotrexateTransaminases

Identifiers

PMID30415610
PMCPMC6587584
OpenAlexW2899885364

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.