Cardiovascular Inflammation Reduction Trial (CIRT)

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

The Cardiovascular Inflammation Reduction Trial (CIRT) is a randomized clinical trial investigating whether taking low-dose methotrexate reduces heart attacks, strokes, or death in people with type 2 diabetes or metabolic syndrome that have had a heart attack or multiple coronary blockages. This trial is funded by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH).

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease
• Intervention / Treatment: Drug: Methotrexate; Drug: Placebo

Detailed Description

While inflammation contributes crucially to atherothrombosis, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will reduce rates of myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients with type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response. CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial that will randomize 7,000 men and women from the United States and Canada. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have either suffered documented myocardial infarction in the past or have angiographically demonstrated multivessel coronary artery disease in the past will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. The target methotrexate dose among those allocated to active therapy is 15 to 20 mg po per week, a dose within the range of that commonly used for the treatment of rheumatoid arthritis. All study participants will additionally receive 1.0 mg oral folate to be taken daily six days per week. LDM complications will be minimized through education programs for all investigators and coordinators, through enhanced communication with study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, pulmonary disease, or other risk factors for toxicity; by conducting an initial 5- to 6-week active-therapy run-in (maximum 8 weeks) designed to eliminate individuals who are either intolerant of or unable to adhere to treatment before randomization; and through regular monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose adjustments while maintaining the study blind, and provide an efficient method to address issues of compliance and follow-up on a cost-effective centralized basis. The primary trial endpoint is the rate of myocardial infarction, stroke, or cardiovascular death. Secondary and tertiary endpoints include all-cause mortality, coronary revascularization, incident congestive heart failure, incident peripheral artery disease, incident venous thrombosis, clinically significant aortic stenosis, incident atrial fibrillation, incident diabetes among those with metabolic syndrome but not diabetes at study entry, and hemoglobin A1c (HbA1c) control among those with diabetes at study entry. The trial is event driven such that in the absence of extreme effects, the trial will conclude after accrual of at least 530 primary endpoints, an effect estimated to provide 90 percent power to detect a 25 percent relative risk reduction. The potential clinical impact of CIRT is broad as it has sufficient power to directly address core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will open major new directions for cardiovascular treatment.

• Study Type: Interventional
• Enrollment (Actual): 4786
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1G3Z4
    • Recherche Clinique Sigma, Inc.
  • British Columbia
    • North Vancouver, British Columbia, Canada, V7M 2H4
      • The Medical Arts Health Research Group
    • Penticton, British Columbia, Canada, V2A 5C8
      • The Medical Arts Health Research Group
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3C 0N2
      • Winnipeg Clinic
  • Ontario
    • Brampton, Ontario, Canada, L6Z 4N5
      • Brampton Research Associates
    • Brampton, Ontario, Canada, L6T 4S5
      • Bramalea Medical Centre
    • Burlington, Ontario, Canada, L7R 4E2
      • Philippe R Beaudry Medicine Professional Corporation
    • Cambridge, Ontario, Canada, N1R7R1
      • Vizel Cardiac Research
    • Chatham, Ontario, Canada, N7L 1C1
      • Dr. Linda Sinnaeve's Office
    • Cornwall, Ontario, Canada, K6H 4M4
      • Scisco Clinical Research
    • Guelph, Ontario, Canada, N1E 5G6
      • Dr. Peter Spadafora Health Center
    • Hamilton, Ontario, Canada, L8L 5G4
      • John Stimac, MD
    • Hamilton, Ontario, Canada, L8P 3A9
      • KMH Cardiology & Diagnostics: Hamilton
    • Hamilton, Ontario, Canada, L8W3J6
      • Dr. William Liang
    • Hawkesbury, Ontario, Canada, K6A 1A1
      • Source Unique Clinic
    • Kitchener, Ontario, Canada, N2M 5NG
      • Dr. Ronald Fowlis
    • London, Ontario, Canada, N6A 5A5
      • University Hospital
    • Mississauga, Ontario, Canada, L4T 4J2
      • Malton Medical Research
    • Mississauga, Ontario, Canada, L5K 2L3
      • KMH Cardiology & Diagnostics: Mississauga
    • Mississauga, Ontario, Canada, L5U 0A6
      • Sewa Ram Singal Medicine Professional Corporation
    • Newmarket, Ontario, Canada, L3Y 8C3
      • Newmarket Cardiology Research Group
    • Newmarket, Ontario, Canada, l3y -8c3
      • Newmarket Cardiology Research Group
    • Niagara Falls, Ontario, Canada, I2E6A6
      • Portage Medical Centre
    • North York, Ontario, Canada, M3N2V6
      • Humber River Regional Hospital
    • Oshawa, Ontario, Canada, L1H 1B9
      • Bakbak Medicine Professional Corporation
    • Oshawa, Ontario, Canada, L1J2K1
      • Dr. James Y. Cha
    • Ottawa, Ontario, Canada, k1y -4w7
      • University of Ottawa Heart Institute
    • Peterborough, Ontario, Canada, K9J0B2
      • Kawartha Cardiology Clinical Trials
    • Pickering, Ontario, Canada, L1V 2A6
      • Steeple Hill Medical Centre
    • Sarnia, Ontario, Canada, N7T 4X3
      • Sarnia Institute of Clinical Research
    • Scarborough, Ontario, Canada, M1E5E9
      • Scarborough Cardiology Research
    • Scarborough, Ontario, Canada, M1PT27
      • Scarborough General Hospital Cardiology Research Associates
    • Scarborough, Ontario, Canada, M1V5P6
      • Milliken Medical Centre
    • Smith Falls, Ontario, Canada, K7A 4W8
      • Canadian Centre for Research on Diabetes
    • St. Catharines, Ontario, Canada, L2S 2Y3
      • Lake Shore Cardiology
    • St. Thomas, Ontario, Canada, N5R 2R4
      • Sardar Medical Clinic
    • Sudbury, Ontario, Canada, P3C 1S8
      • G.S. Cardiac Lab Medicine Professional Corp
    • Sudbury, Ontario, Canada, P3E 3B8
      • Dr. R. Labonte Professional Med Corp
    • Sudbury, Ontario, Canada, P3E 3C6
      • Dr. G. Garrioch, Independent Practice
    • Thedford, Ontario, Canada, N0M 2N0
      • Dr. Laurence Gibbs Medicine Professional Corp.
    • Tillsonburg, Ontario, Canada, N4G 5A7
      • Tillsonburg Medical Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
    • Toronto, Ontario, Canada, M3M 0B2
      • Humber River Hospital
    • Toronto, Ontario, Canada, M9N 2A7
      • Weston Road Medical Clinic
    • Whitby, Ontario, Canada, L1N 2L1
      • Dr. Nigel Jagan Medicine Professional Corporation
    • Windsor, Ontario, Canada, N8X 1L9
      • Dr. Nwadiaro Medicine Professional Corp
  • Quebec
    • Brossard, Quebec, Canada, J4X1S4
      • Viacar Recherche Clinique Inc.
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
    • Chicoutimi, Quebec, Canada, G7H 7Y8
      • Q&T Research Chicoutimi
    • Greenfield Park, Quebec, Canada, J4V2G8
      • Viacar Recherche Clinique Inc.
    • Montreal, Quebec, Canada, H2W 1T8
      • CHUM Hôtel-Dieu
    • Quebec City, Quebec, Canada, G1V 4G5
      • IUCPQ
    • Québec, Quebec, Canada, G3K 2P8
      • Alpha Recherche Clinique
    • Saint-Jean-sur-Richelieu, Quebec, Canada, j3a-1c3
      • CardioVasc HR
    • Saint-Lambert, Quebec, Canada, J4P 2H4
      • ViaCar Recherche Clinique Inc
    • St. Lambert, Quebec, Canada, J4P 2J2
      • Viacar Recherche Clinique
    • Terrebonne, Quebec, Canada, J6V 2H2
      • Hopital Pierre-Le Gardeur
• Puerto Rico
  • Bayamón, Puerto Rico, 00961
    • Instituto Sanacoop
  • Caguas, Puerto Rico, 00727
    • San Juan Bautista School of Medicine
  • Canovanas, Puerto Rico, 00729
    • Norma S. Severino-Pacheco, MD
  • Ponce, Puerto Rico, 00717
    • Cardiometabolic Research Center
  • San Juan, Puerto Rico, 00926-2832
    • Miguel Sosa-Padilla, MD
  • Toa Baja, Puerto Rico, 00949
    • Yolanda Sierra Quinones, MD
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Fort Payne, Alabama, United States, 35967
      • Appalachian Research Associates
    • Guntersville, Alabama, United States, 35976
      • Avant Research Associates, LLC
    • Huntsville, Alabama, United States, 35801
      • Saadat Ansari MD LLC
    • Mobile, Alabama, United States, 36617
      • University of South Alabama: Division of Clinical Research
  • Arizona
    • Cottonwood, Arizona, United States, 86326
      • Heart Vascular of Northern Arizona
    • Mesa, Arizona, United States, 85206
      • CardioVascular Associates of Mesa
    • Phoenix, Arizona, United States, 85032
      • Arizona Arthritis & Rheumatology Research
    • Scottsdale, Arizona, United States, 85258
      • Scottsdale Medical Imaging
    • Scottsdale, Arizona, United States, 85258
      • The Heart Clinic
    • Tucson, Arizona, United States, 85723
      • Southern Arizona VA Health Care System
    • Tucson, Arizona, United States, 85718
      • Pima Heart
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Arkansas Heart Hospital
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cardiology
  • California
    • Anaheim, California, United States, 92801
      • Oracle Clinical Research, Inc.
    • Culver City, California, United States, 90230
      • Medical Group of Culver City
    • Fairfield, California, United States, 94533
      • Touro University California- Solano County Affiliated Clinics
    • Fresno, California, United States, 93701
      • University of California San Francisco
    • Fresno, California, United States, 93703
      • VACCHCS
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • La Jolla, California, United States, 92037
      • UCSD Sulpizio Cardiovascular Center
    • La Quinta, California, United States, 92253
      • Desert Medical Care & Wellness
    • Lancaster, California, United States, 93534
      • Kumar Medical Corporation
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health
    • Loma Linda, California, United States, 92357
      • VA Loma Linda Healthcare System
    • Long Beach, California, United States, 90807
      • Long Beach Center For Clinical Research
    • Long Beach, California, United States, 90813
      • Cardiovascular Innovation and Research
    • Los Alamitos, California, United States, 90720
      • Los Alamitos Cardiovascular
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90022
      • Eastside Clinical Research Associates
    • Los Angeles, California, United States, 90004
      • Faye Montegrande Md. Clinical Research
    • Los Angeles, California, United States, 90033
      • Salman Khan A. Medical Corporation
    • Los Angeles, California, United States, 90049
      • West LA VA Medical Center
    • Mather, California, United States, 95655
      • VA Northern California Health Care
    • Northridge, California, United States, 91325
      • Valley Clinical Trials, Inc.
    • Orange, California, United States, 92868
      • University of CA Irvine Medical Center
    • Orange, California, United States, 92868
      • Orange County Heart Institute & Research
    • Oxnard, California, United States, 93030
      • Diverse Research Solutions
    • Pasadena, California, United States, 91105
      • Huntington Memorial Hospital
    • Salinas, California, United States, 93901
      • Central Coast Cardiology
    • San Diego, California, United States, 92123
      • San Diego Cardiac Center
    • San Diego, California, United States, 92161
      • Veterans Affairs San Diego Healthcare System
    • San Diego, California, United States, 92117
      • Ritchken and First MDs
    • San Diego, California, United States, 92121
      • Foundation for Cardiovascular Medicine
    • San Diego, California, United States, 92103
      • Richard G. Friedman, MD
    • San Francisco, California, United States, 94110
      • UCSF at Zuckerberg SF General Hospital
    • Santa Ana, California, United States, 92704
      • Coastal Heart Medical Group, Inc.
    • Santa Maria, California, United States, 93454
      • Comprehensive Cardiovascular Care
    • Stockton, California, United States, 95210
      • Pacific Heart and Vascular Medical Group
    • Thousand Oaks, California, United States, 91360
      • Manoj D. Aswani M.D.
    • Vallejo, California, United States, 94592
      • Touro University California- Solano Public Health Affiliated Clinics
  • Colorado
    • Colorado Springs, Colorado, United States, 80910
      • Munni R. Selagamsetty, Md, Pc
    • Denver, Colorado, United States, 80218
      • Vijay - Aurora Denver Cardiology
    • Fort Collins, Colorado, United States, 80528
      • Colorado Health Medical Group Heart Center of the Rockies
    • Fort Collins, Colorado, United States, 80528
      • Medical Center of the Rockies Research
    • Parker, Colorado, United States, 80134
      • Unrein - Rocky Vista University Health Center
  • Connecticut
    • Bridgeport, Connecticut, United States, 06610
      • Bridgeport Hospital
    • Bridgeport, Connecticut, United States, 06606
      • Connecticut Heart and Vascular Center
  • Delaware
    • Newark, Delaware, United States, 19713
      • Cardiology Physicians/Red Clay Research
  • District of Columbia
    • Washington, District of Columbia, United States, 20024
      • Boisey Barnes MD, PC
    • Washington, District of Columbia, United States, 20037
      • GWU Medical Faculty Associatin, Inc.
  • Florida
    • Aventura, Florida, United States, 33180
      • Pianko - Aventura Research Center, LLC
    • Boca Raton, Florida, United States, 33434
      • North Ridge Heart Associates
    • Clearwater, Florida, United States, 33765
      • St. Francis Medical Institute
    • Coral Gables, Florida, United States, 33134
      • Gonzalez MD & Aswad MD Health Ser
    • Cutler Bay, Florida, United States, 33157
      • American Research Institute, Inc.
    • Daytona Beach, Florida, United States, 32114
      • Daytona Heart Group
    • DeLand, Florida, United States, 32720
      • Daytona Heart Group
    • Delray Beach, Florida, United States, 33484
      • Seidman Clinical Trials
    • Delray Beach, Florida, United States, 33484
      • Steven Cohen MD
    • Doral, Florida, United States, 33166
      • International Research Partners, LLC
    • Doral, Florida, United States, 33126
      • Infinite Clinical Research
    • Doral, Florida, United States, 33178
      • Medical Research Institute at Doral, Inc.
    • Eustis, Florida, United States, 32726
      • Lake Internal Medicine Assocaties
    • Fort Lauderdale, Florida, United States, 33308
      • Invesclinic
    • Fort Myers, Florida, United States, 33907
      • Primary Care Associates
    • Fort Myers, Florida, United States, 33908
      • Lee Physician Group
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Gainesville, Florida, United States, 32605
      • The Cardiac and Vascular Institute
    • Hialeah, Florida, United States, 33010
      • Qway Research
    • Hialeah, Florida, United States, 33016
      • Best Quality Research, Inc.
    • Hialeah, Florida, United States, 33010
      • State of the Art Research
    • Hialeah, Florida, United States, 33012
      • Healing Touch C&C Research
    • Hialeah, Florida, United States, 33012
      • Luzmed Clinical Research Institute
    • Hialeah, Florida, United States, 33012
      • Viviana Perez MD Research & Cosmetics
    • Hialeah, Florida, United States, 33013
      • Elite Cardiac Research Center LLC
    • Hialeah, Florida, United States, 33013
      • Nova Clinical Research Clinic
    • Hollywood, Florida, United States, 33021
      • South Florida Research Solutions, LLC
    • Homestead, Florida, United States, 33030
      • John Gutleber Medical Research Office
    • Jupiter, Florida, United States, 33458
      • Cardiovascular Medical Associates of Palm Beach
    • Kissimmee, Florida, United States, 34758
      • Hope Clinical Research
    • Kissimmee, Florida, United States, 34759
      • SIH Research, LLC
    • Miami, Florida, United States, 33176
      • Vista Health Research, LLC
    • Miami, Florida, United States, 33155
      • Sanitas Research
    • Miami, Florida, United States, 33176
      • South Florida Research Group, LLC
    • Miami, Florida, United States, 33155
      • Gad Research Center
    • Miami, Florida, United States, 33134
      • Team Medical Research
    • Miami, Florida, United States, 33122
      • Medical Research Center of Florida
    • Miami, Florida, United States, 33126
      • LG Diagnostics, Inc.
    • Miami, Florida, United States, 33126
      • St. Paul Medical Research Center, Inc.
    • Miami, Florida, United States, 33144
      • Paradise Clinical Research, LLC
    • Miami, Florida, United States, 33155
      • Innovation Research Institute, Inc.
    • Miami, Florida, United States, 33165
      • Segui - Med Care Research
    • Miami, Florida, United States, 33186
      • D De La Vega MD Research Group
    • Miami Lakes, Florida, United States, 33014
      • Lakes Research, LLC
    • Miami Lakes, Florida, United States, 33014
      • Veritas Research Corp.
    • Miami Springs, Florida, United States, 33166
      • Ocean Blue Medical Research Center
    • Naples, Florida, United States, 34102
      • Southwest Florida Research, LLC
    • Orlando, Florida, United States, 32806
      • Orlando Healthy Heart Institute
    • Palm Beach Gardens, Florida, United States, 33410
      • Palm Beach Gardens Research Center, LLC
    • Pembroke Pines, Florida, United States, 33024
      • Broward Research Center
    • Pembroke Pines, Florida, United States, 33024
      • Pioneer Clinical Research
    • Pembroke Pines, Florida, United States, 33204
      • Sandoval - Broward Research Center
    • Saint Petersburg, Florida, United States, 33705
      • Bay Area Heart Center: 49th Street
    • Saint Petersburg, Florida, United States, 33705
      • Bay Area Heart Center: 7th Avenue
    • Sweetwater, Florida, United States, 33172
      • Lenus Research & Medical Group
    • Tamarac, Florida, United States, 33321
      • DBC Research
    • Weeki Wachee, Florida, United States, 34607
      • ASCLEPES Research Centers
    • Wesley Chapel, Florida, United States, 33544
      • Gupta - Premier Heart and Vascular Center
  • Georgia
    • Athens, Georgia, United States, 30606
      • Athens Regional Medical Center
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
    • Atlanta, Georgia, United States, 30033
      • Atlanta Veterans Affairs Medical Center
    • Atlanta, Georgia, United States, 30308
      • Laureate Medical Group at Northside
    • Atlanta, Georgia, United States, 30308
      • Synergy Therapeutic Partners
    • Cumming, Georgia, United States, 30041
      • Atlanta Heart Specialists, LLC
    • Dalton, Georgia, United States, 30720
      • Heart and Rhythm Specialists
    • Dunwoody, Georgia, United States, 30338
      • Albert F. Johary MD, PC
    • Riverdale, Georgia, United States, 30274
      • Infinite Clinical Trials
    • Smyrna, Georgia, United States, 30082
      • Atlanta Vanguard Medical Associates
    • Suwanee, Georgia, United States, 30024
      • Herman Clinical Research, LLC
    • Tucker, Georgia, United States, 30084
      • Atlanta Heart Specialists, LLC
    • Vidalia, Georgia, United States, 30474
      • Cardiology Associates of Vidalia, P.C.
  • Hawaii
    • Honolulu, Hawaii, United States, 96819
      • VA Pacific Islands Health Care System
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Idaho Cardiology Associates
    • Idaho Falls, Idaho, United States, 83404
      • Clinical Research Prime
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Northwest Heart Clinical Research
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Chicago, Illinois, United States, 60657
      • Advocate Med Group-Heart & Vascular Of Illinois
    • Normal, Illinois, United States, 61761
      • Illinois Heart & Lung Research Center, Sc
    • North Chicago, Illinois, United States, 60064
      • Captain James A. Lovell Federal Health
    • Olympia Fields, Illinois, United States, 60461
      • Specialty Physicians of Illinois, LLC
    • Rock Island, Illinois, United States, 61201
      • Advanced Cardiovascular Consultants
  • Indiana
    • Dyer, Indiana, United States, 46311
      • Cardiospecialists, LTD
    • Evansville, Indiana, United States, 47714
      • Martin - Martin Family Practice and Research
    • Indianapolis, Indiana, United States, 46202
      • Krannert Institute of Cardiology
    • Indianapolis, Indiana, United States, 46227
      • Community Hospital South
    • Indianapolis, Indiana, United States, 46237
      • Indiana Heart Physicians
    • Muncie, Indiana, United States, 47303
      • Medical Consultants, Pc
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Iowa Heart Center
  • Kansas
    • Overland Park, Kansas, United States, 66209
      • Stahl - Midwest Heart & Vascular Specialists
    • Wichita, Kansas, United States, 67203
      • Professional Research Network of KS
    • Wichita, Kansas, United States, 67230
      • Robert J. Dole VAMC
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • Robley Rex VAMC
    • Louisville, Kentucky, United States, 40202
      • Stoddard - University of Louisville
    • Louisville, Kentucky, United States, 40213
      • Bays - L-MARC Research Center
    • Owensboro, Kentucky, United States, 42303
      • Research Integrity LLC
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Dorothy H. Banish, MD, APMC Study Group
    • Crowley, Louisiana, United States, 70526
      • Avant Research Associates, LLC
    • Hammond, Louisiana, United States, 70403
      • North Oaks Cardiology
    • Marrero, Louisiana, United States, 70072
      • American Clinical Research, LLC
    • Natchitoches, Louisiana, United States, 71457
      • Otis Barnum D.O.P.C.
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Office of Health Research
    • Shreveport, Louisiana, United States, 71101
      • Veterans Affairs Medical Center Shreveport
  • Maine
    • Auburn, Maine, United States, 04210
      • Maine Research Associates
    • Bangor, Maine, United States, 04401
      • Paul A. Shapero, M.D.
    • Biddeford, Maine, United States, 04005
      • Southern Maine Health Care
    • Portland, Maine, United States, 04101
      • Intermed, PA
    • South Portland, Maine, United States, 04106
      • Maine Medical Partners Maine Health Cardiology
    • Westbrook, Maine, United States, 04092
      • Maine Centers for Healthcare
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Center for Thrombosis Research
    • Charlotte Hall, Maryland, United States, 20622
      • St. Mary's Medical Center
    • Clinton, Maryland, United States, 20735
      • Calvert Memorial Hospital
    • Prince Frederick, Maryland, United States, 20678
      • Shah Associates, MD, LLC
    • Salisbury, Maryland, United States, 21804
      • Peninsula Cardiology Associates
    • Towson, Maryland, United States, 21204
      • IRC Clinics
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
    • Boston, Massachusetts, United States, 02135
      • St. Elizabeth's Medical Center
    • Boston, Massachusetts, United States, 02214
      • MGH Cardiology
    • Burlington, Massachusetts, United States, 01805
      • Lahey Hospital and Medical Center
    • Chelsea, Massachusetts, United States, 02150
      • Massachusetts General Hospital - Chelsea Health Care Center
    • Haverhill, Massachusetts, United States, 01830
      • Pentucket Medical Associates, Inc.
    • Leeds, Massachusetts, United States, 01053
      • VA Central Western Massachusetts Healthca
    • Milton, Massachusetts, United States, 02186
      • South Shore Internal Medicine
    • Peabody, Massachusetts, United States, 02149
      • Lahey Medical Center
    • Salem, Massachusetts, United States, 01907
      • North Shore Cardiovascular Associates
    • Worcester, Massachusetts, United States, 01608
      • Reliant Medical Group
  • Michigan
    • Alpena, Michigan, United States, 49707
      • Endeavor Medical Research
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48201
      • John D. Dingell Veterans Affairs Medical Center
    • Detroit, Michigan, United States, 48201
      • Trace Research Group at Wayne State University
    • Flint, Michigan, United States, 48503
      • Flint Clinical Research
    • Flint, Michigan, United States, 48504
      • Apex Medical Research MI, Inc.
    • Garden City, Michigan, United States, 48135
      • Garden City Hospital
    • Grand Blanc, Michigan, United States, 48439
      • Genesys Regional Medical Center
    • Hamtramck, Michigan, United States, 48212
      • National Clinical LLC
    • Rochester Hills, Michigan, United States, 48307
      • Academic Cardiology Associates PC
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Health Center
    • Saginaw, Michigan, United States, 48602
      • Covenant Medical Center, INC.
    • Saginaw, Michigan, United States, 48609
      • Mid-Michigan Heart & Vascular Center
  • Minnesota
    • Saint Cloud, Minnesota, United States, 56303
      • Centra Care Heart & Vascular Center at St. Cloud Hospital
    • Saint Paul, Minnesota, United States, 55102
      • United Heart and Vascular Clinic
  • Mississippi
    • Gulfport, Mississippi, United States, 39501
      • Gulfside Clinical Research, LLC
    • Jackson, Mississippi, United States, 39216
      • University of MS Medical Center
    • Port Gibson, Mississippi, United States, 39150
      • David M. Headley M.D. PA Planters Clinic
    • Southaven, Mississippi, United States, 38671
      • Stern Cardiovascular Foundation, Inc.
  • Missouri
    • Bridgeton, Missouri, United States, 63044
      • Center for Advanced Medicine and Research LLC
    • Columbia, Missouri, United States, 65212
      • Clinical Research Center University of Missouri
    • Festus, Missouri, United States, 63028
      • Quantum Research LLC
    • Independence, Missouri, United States, 64057
      • Midwest Cardiology Associates
    • Joplin, Missouri, United States, 64804
      • Freeman Health System
    • Kansas City, Missouri, United States, 64128
      • VA Medical Center Kansas City
    • Osage Beach, Missouri, United States, 65065
      • Lake Regional Cardiovascular Institute
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63122
      • Consult and Research Associates
    • Saint Louis, Missouri, United States, 63119
      • Clinical Investigators LLC
    • Saint Louis, Missouri, United States, 63106
      • VA St. Louis Health Care System (VASTLHCS)
    • Saint Louis, Missouri, United States, 63110
      • SLUCare Cardiology
    • Saint Peters, Missouri, United States, 63303
      • Center for Advanced Medicine and Research
    • Springfield, Missouri, United States, 65807
      • Mercy Medical Research Institute
    • Springfield, Missouri, United States, 65807
      • CoxHealth: Wheeler Heart & Vascular Center
  • Montana
    • Great Falls, Montana, United States, 59420
      • Great Falls Clinic Clinical Research Deptartment
    • Missoula, Montana, United States, 59801
      • Cone - Montana Medical Research
  • Nebraska
    • La Vista, Nebraska, United States, 68128
      • Barrett Clinic, P.C.
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68131
      • Alegent Creighton Health
    • Omaha, Nebraska, United States, 68114
      • Heart Consultants
  • Nevada
    • Las Vegas, Nevada, United States, 89146
      • Red Rock Clinical Research, LLC
    • Las Vegas, Nevada, United States, 89102
      • Internal Medicine Clinic
    • Reno, Nevada, United States, 89502
      • Sierra Nevada Health Care System
    • Reno, Nevada, United States, 89503
      • Renown Inst for Heart & Vasc Health
  • New Hampshire
    • Nashua, New Hampshire, United States, 03060
      • Lahey Cardiology
  • New Jersey
    • Flanders, New Jersey, United States, 07836
      • Family Health at Mount Olive
    • Hillsborough, New Jersey, United States, 08844
      • Cardiocare
    • Linden, New Jersey, United States, 07063
      • New Jersey Heart
    • Neptune, New Jersey, United States, 07753
      • Jersey Shore University Medical Center
    • New Brunswick, New Jersey, United States, 08901
      • Cardiovascular Institute
    • North Bergen, New Jersey, United States, 07047
      • Palisade Medical Center
    • Ridgewood, New Jersey, United States, 07450
      • The Valley Hospital
    • Robbinsville, New Jersey, United States, 08691
      • Mercer Bucks Cardiology
    • Somerset, New Jersey, United States, 08873
      • Cardio Metabolic Institute
    • Teaneck, New Jersey, United States, 07666
      • Holy Name Medical Center, Inc.
    • Wayne, New Jersey, United States, 07470
      • Total Cardiology Care, LLC
    • Westwood, New Jersey, United States, 07675
      • Westwood Cardiology Associates
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • Presbyterian Heart Group
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Albany, New York, United States, 12208
      • Albany Stratton VA Medical Center
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Bronx, New York, United States, 10461
      • Novel Research of New York, LLC
    • Brooklyn, New York, United States, 11203
      • Brown - SUNY Downstate Medical Center
    • Buffalo, New York, United States, 14215
      • Buffalo Heart group
    • Cooperstown, New York, United States, 13326
      • Bassett Healthcare Network
    • Cortlandt Manor, New York, United States, 10567
      • NYU Hudson Valley Cardiology
    • Flushing, New York, United States, 11355
      • NYHQ
    • Jamaica, New York, United States, 11418
      • Jamaica Hospital Medical Center
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • Mineola, New York, United States, 11501
      • Long Island Heart Associates
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New Hyde Park, New York, United States, 11577
      • Queens Long Island Medical Group
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10013
      • Chinatown Cardiology, PC
    • New York, New York, United States, 10021
      • Weill Cornell Medical College and NY Presbyterian
    • North Massapequa, New York, United States, 11758
      • DiGiovanna Institute for Medical Education And Research
    • Plattsburgh, New York, United States, 12901
      • Champlain Valley Physician Hospital
    • Schenectady, New York, United States, 12309
      • Cardiology Associates of Schenectady
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Clinical Study Center of Asheville
    • Charlotte, North Carolina, United States, 28205
      • Gaffney Health Services
    • Charlotte, North Carolina, United States, 28215
      • Carolinas Research Center
    • Charlotte, North Carolina, United States, 28204
      • Metrolina Internal Medicine
    • Elizabeth City, North Carolina, United States, 27909
      • Eastern Carolina Cardiovascular, PA
    • Greenville, North Carolina, United States, 27834
      • Eastern Cardiology
    • Lenoir, North Carolina, United States, 28645
      • Northside Clinical Research
    • Mooresville, North Carolina, United States, 28117
      • Lake Shore Clinical Research, LLC.
    • Morehead City, North Carolina, United States, 28557
      • Carteret Medical Group
    • Morganton, North Carolina, United States, 28655
      • Cardiology Associates of Carolinas, PA
    • New Bern, North Carolina, United States, 28562
      • Eastern Nephrology Associates, PLLC
    • Rocky Mount, North Carolina, United States, 27804
      • Boice Willis Clinic
    • Sanford, North Carolina, United States, 27330
      • Sanford Cardiology
    • Wilson, North Carolina, United States, 27893
      • Natalie A. Doyle, MD, PA
  • North Dakota
    • Grand Forks, North Dakota, United States, 58201
      • Altru Health System Rehab Center
  • Ohio
    • Akron, Ohio, United States, 44307
      • Akron General Medical Center
    • Athens, Ohio, United States, 45701
      • Ohio University Heritage College of Osteopathic Medicine
    • Canton, Ohio, United States, 44718
      • Diabetes and Endocrinology Associates of Stark Cit
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Research Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43235
      • Optimed Research, LTD
    • Dayton, Ohio, United States, 45414
      • Dayton Heart Center
    • Dayton, Ohio, United States, 45428
      • Dayton Veteran Affairs Medical Center
    • Lancaster, Ohio, United States, 43130
      • Colonnade Medical Group
    • Middletown, Ohio, United States, 45044
      • Middletown Cardiovascular Associates
    • Toledo, Ohio, United States, 43606
      • Comprehensive Heart Care, Inc.
    • Westerville, Ohio, United States, 43081
      • Mount Carmel Clinical Cardiovascular Care
    • Westlake, Ohio, United States, 44154
      • Premier Physicians
    • Wooster, Ohio, United States, 44691
      • Wooster Heart Group
  • Oklahoma
    • Lindsay, Oklahoma, United States, 73052
      • Unity Clinical Research
    • Oklahoma City, Oklahoma, United States, 73103
      • COR Clinical Research, LLC
    • Oklahoma City, Oklahoma, United States, 73129
      • Today Clinical Research
    • Oklahoma City, Oklahoma, United States, 73134
      • Cardiovascular Health Clinic
    • Oklahoma City, Oklahoma, United States, 73104
      • Thadani - VA Medical Center Oklahoma City, OK
    • Tulsa, Oklahoma, United States, 74127
      • Oklahoma State University Center for Health Sciences
  • Oregon
    • Corvallis, Oregon, United States, 97330
      • Samaritan Health Services
    • Medford, Oregon, United States, 97504
      • Southern Oregon Cardiology, LLC
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Center for Clinical Res. Abington Health
    • Bethlehem, Pennsylvania, United States, 18018
      • St. Luke's University Hospital
    • Bristol, Pennsylvania, United States, 19007
      • Renu-Ca Research Institute, Lower Bucks Hospital
    • Broomall, Pennsylvania, United States, 19008
      • Main Line Health Center, Broomall
    • Camp Hill, Pennsylvania, United States, 17011
      • Spirit Physician Services, Inc
    • Chambersburg, Pennsylvania, United States, 17201
      • The Chambersburg Hospital
    • Doylestown, Pennsylvania, United States, 18901
      • Central Bucks Cardiology
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
    • Ephrata, Pennsylvania, United States, 17522
      • Heart Specialists of Lancaster County
    • Erie, Pennsylvania, United States, 16502
      • Saint Vincent Consultants in Cardiovascular Diseases, LLC
    • Feasterville, Pennsylvania, United States, 19053
      • Feasterville Family Healthcare Center
    • Glen Mills, Pennsylvania, United States, 19342
      • Christiana Care Health System
    • Harrisburg, Pennsylvania, United States, 17110
      • Pinnacle Health Cardiovascular Institute
    • Lansdowne, Pennsylvania, United States, 19050
      • George Isajiw, MD
    • Morrisville, Pennsylvania, United States, 19067
      • Bucks County Clinical Research
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
    • Sellersville, Pennsylvania, United States, 18960
      • Lehigh Valley Health Services
    • Uniontown, Pennsylvania, United States, 15401
      • Pish Medical Associates, Inc.
    • Whitehall, Pennsylvania, United States, 18052
      • Lehigh Valley Family Practice
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Wilkes-Barre VA Medical Center
  • Rhode Island
    • Cumberland, Rhode Island, United States, 02864
      • Partners in Clinical Research
    • Lincoln, Rhode Island, United States, 02865
      • Ocean State Clinical Research Prtnr
    • Pawtucket, Rhode Island, United States, 02860
      • Memorial Hospital of Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital
    • Providence, Rhode Island, United States, 02908
      • Ocean State Research Institute, Inc
  • South Carolina
    • Columbia, South Carolina, United States, 29204
      • South Carolina Heart Center
    • Columbia, South Carolina, United States, 29223
      • Amistad Research Center, LLC
    • Indian Land, South Carolina, United States, 29707
      • Charlotte Hearts
    • Irmo, South Carolina, United States, 29063
      • Miller - SC Internal Medicine Associates.: Irmo
    • Pawleys Island, South Carolina, United States, 29585
      • Inlet Cardiopulmonary & Associates
    • Spartanburg, South Carolina, United States, 29301
      • Fusion Clinical Research of Spartanburg
    • Spartanburg, South Carolina, United States, 29302
      • Palmetto Research Center, LLC
  • Tennessee
    • Chattanooga, Tennessee, United States, 37409
      • New Phase Research & Development
    • Fayetteville, Tennessee, United States, 37334
      • Parkway Medical Group
    • Germantown, Tennessee, United States, 38138
      • Stern Cardiovascular Foundation, Inc.
    • Jackson, Tennessee, United States, 38305
      • Kore Cardiovascular Research Institutue
    • Knoxville, Tennessee, United States, 37909
      • New Phase Research & Development
    • Knoxville, Tennessee, United States, 37917
      • Cardiovascular Research of Knoxville
    • Memphis, Tennessee, United States, 38104
      • Ramanathan - VAMC Memphis
    • Nashville, Tennessee, United States, 37208
      • Clinical Research Center Meharry Medical College
  • Texas
    • Austin, Texas, United States, 78704
      • Avant Research Associates LLC
    • Austin, Texas, United States, 78745
      • Texas Heart and Vascular Research, LLC
    • Beaumont, Texas, United States, 77702
      • Southeast TX Clinical Research Center
    • Big Spring, Texas, United States, 79720
      • Cornerstone Family Medicine
    • Carrollton, Texas, United States, 75006
      • iMD Medical Center
    • Carrollton, Texas, United States, 75010
      • Texas Health Physicians Group
    • Dallas, Texas, United States, 75231
      • Cardiovascular Research Institute of Dallas
    • Dallas, Texas, United States, 75231
      • North Texas Health Center
    • Dallas, Texas, United States, 75235
      • The Heart Center of Dallas
    • DeSoto, Texas, United States, 75115
      • Global Medical Research
    • Fort Worth, Texas, United States, 76104
      • The Medical Group Of Texas
    • Fort Worth, Texas, United States, 76107
      • Texas Health Physicians Group
    • Haltom City, Texas, United States, 76117
      • T&R Clinic, P.A.
    • Houston, Texas, United States, 77030
      • Michele P. Sartori, MD
    • Katy, Texas, United States, 77494
      • Grand Medical Care
    • Killeen, Texas, United States, 76543
      • Team Research of Central Texas
    • Kingwood, Texas, United States, 77339
      • Houston Heart and Vascular Associates
    • Marshall, Texas, United States, 75670
      • Grace Research, LLC
    • McAllen, Texas, United States, 78503
      • Valley Heart Consultants
    • Mineral Wells, Texas, United States, 76067
      • Heart Center, Palo Pinto General Hospital
    • Mission, Texas, United States, 78572
      • Valley Central Research Inc
    • North Richland Hills, Texas, United States, 76180
      • North Hills Medical Research, Inc
    • Palestine, Texas, United States, 75801
      • Grace Research, LLC
    • Port Arthur, Texas, United States, 77640
      • Avant Research Associates, LLC
    • San Antonio, Texas, United States, 78229
      • Schnitzler Cardiovascular Consultants
    • San Antonio, Texas, United States, 78212
      • Santoscoy - Health Texas Research Institute
    • San Antonio, Texas, United States, 78229
      • Element Research Group
    • San Antonio, Texas, United States, 78268
      • San Antonio Endovascular & Heart Institute
    • Sugar Land, Texas, United States, 77478
      • Acacia Medical Research Institute
    • Sugar Land, Texas, United States, 77478
      • Health Plus Clinical Research
    • Tomball, Texas, United States, 77375
      • Lone Star Heart and Vascular Center
    • Tomball, Texas, United States, 77375
      • Northwest Houston Clinical Research
    • Waco, Texas, United States, 76710
      • Hillcrest Family Health Center
  • Utah
    • Layton, Utah, United States, 84041
      • Utah Cardiology, P.C.
    • Salt Lake City, Utah, United States, 84108
      • Utah Diabetes Center
  • Vermont
    • White River Junction, Vermont, United States, 05009
      • VA Medical Center, White River Junction
  • Virginia
    • Burke, Virginia, United States, 22015
      • Burke Internal Medicine & Research
    • Falls Church, Virginia, United States, 22044
      • Seven Corners Medical Research Center
    • Hampton, Virginia, United States, 23666
      • Hampton Family Practice Research
    • Hampton, Virginia, United States, 23666
      • Tidewater Physicians Multispecialty Group
    • Manassas, Virginia, United States, 20110
      • Manassas Clinical Research Center
    • Manassas, Virginia, United States, 20109
      • Virginia Cardiovascular Associates
    • Mechanicsville, Virginia, United States, 23116
      • Tucker Cardiology Associates, P.C.
    • Newport News, Virginia, United States, 23606
      • TPMG Clinical Research
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
    • Roanoke, Virginia, United States, 24014
      • Roanoke Heart Institute PLC
    • Woodbridge, Virginia, United States, 22192
      • Cardinal Internal Medicine Associates
    • Yorktown, Virginia, United States, 23690
      • Tidewater Physicians Multispecialty Group
  • Washington
    • Port Orchard, Washington, United States, 98366
      • Frandsen Family Medicine DBA Sound Medi
    • Spokane, Washington, United States, 99202
      • Premier Clinical Research
    • Spokane, Washington, United States, 99208
      • Northside Internal Medicine
    • Spokane, Washington, United States, 99204
      • Kootenai Heart Clinics, LLC
    • Vancouver, Washington, United States, 98684
      • Northwest Medical Associates, P.S.
  • Wisconsin
    • Green Bay, Wisconsin, United States, 54115
      • Cardiology Associates of Bellin Health
    • Madison, Wisconsin, United States, 53715
      • University of Wisconsin
    • Madison, Wisconsin, United States, 53715
      • Dean Foundation
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center
    • Milwaukee, Wisconsin, United States, 53211
      • Columbia St. Mary's

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years at screening

• Documented past history of myocardial infarction OR past evidence of multivessel coronary artery disease by angiography.

  • To qualify on the basis of past history of myocardial infarction, the event must be documented either by hospital records or by evidence on current ECG of Q waves in two contiguous leads and/or an imaging test demonstrating wall motion abnormality or scar. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.
  • To qualify on the basis of multivessel coronary disease, there must be past angiographic evidence of atherosclerosis in at least 2 major epicardial vessels defined either as the presence of a stent, a coronary bypass graft, or an angiographic lesion of 60% or greater. Left main coronary artery disease that has been revascularized with a stent or bypass graft will qualify as multivessel disease, as will the presence of a 50% or greater isolated left main stenosis. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.
• History of type 2 diabetes or metabolic syndrome at time of study enrollment
• Willingness to participate as evidenced by signing the study informed consent

Exclusion Criteria:

• Prior history of chronic infectious disease, tuberculosis, or severe fungal disease; chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years; known HIV positive; life expectancy of < 3 years;
• Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn's disease
• White blood cell count < 3,500/ul, hematocrit < 32 percent, or platelet count < 75,000/ul
• Liver transaminase levels (AST or ALT) >upper limit of normal (ULN) or albumin < the lower limit of normal (LLN);
• Creatinine clearance < 40 ml/min as estimated with the Cockcroft-Gault equation;
• History of alcohol abuse or unwillingness to limit alcohol consumption to less than 4 drinks per week
• Women of child bearing potential, even if they are currently using contraception, and women intending to breastfeed.
• Men who plan to father children during the study period or who are unwilling to use effective forms of contraception.
• Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible;
• Current indication for methotrexate therapy;
• Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers. Eligible study participants will be encouraged to have up to date pneumococcal and influenza vaccinations as recommended based on their age and underlying medical conditions.
• Chest X-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. For participants who do not have a chest X-ray in the prior 12 months, a chest X-ray will be obtained at baseline as part of the study protocol.
• New York Heart Association Class IV congestive heart failure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methotrexate; Methotrexate: Tablet, Oral, Target dose 15-20mg weekly plus 1.0 mg folic acid 6 days/week	Drug: Methotrexate; Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week; Other Names: Trexall, TEVA Inc (brand of methotrexate)
Placebo Comparator: Placebo; Placebo: Tablet, Oral weekly plus 1.0mg folic acid 6 days/week	Drug: Placebo; Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Major Adverse Cardiovascular Events	The first occurrence of Major Adverse Cardiovascular Event which is defined as the occurrence of one or more of the following: Cardiovascular Death, Non-Fatal Myocardial Infarction or Non-Fatal Stroke.	From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization	The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization.	From randomization to trial end (April 2, 2018) - up to a maximum of 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With All-cause Mortality	Subjects who died from any cause.	From randomization to the trial end (April 2, 2018) up to a maximum of 5 years
Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization	The first occurrence of Major Adverse Cardiovascular Event or Any Coronary Revascularization.	From randomization to the trial end (April 2, 2018) - up to a maximum of 5 years
Number of Subjects With Hospitalization for Congestive Heart Failure	The first occurrence of Hospitalization for Congestive Heart Failure	From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality	The first occurrence of Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality.	From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Number of Subjects With New Onset Type 2 Diabetes	New onset type 2 diabetes among those without diabetes at baseline. Baseline diabetes is defined as any of the following prior to randomization: clinician report of diabetes, use of antidiabetic medication, hbA1c >=6.5 or fasting plasma glucose >=126.	From randomization to the trial end (April 2, 2018) - up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization	The first occurrence of hospitalization for unstable angina that led to unplanned coronary revascularization	From randomization to the trial end (April 2, 2018) up to 5 years
Number of Subjects With Coronary Revascularization	The first occurrence of coronary revascularization	From randomization to trial end (April 2, 2018) up to 5 years
Number of Subjects With Peripheral Artery Disease	The first occurrence of new or worsening of peripheral artery disease	From randomization to the trial end (April 2, 2018) - up to 5 years
Number of Subjects With Deep Vein Thrombosis or Pulmonary Embolism	The first occurrence of symptomatic deep vein thrombosis or pulmonary embolism	From randomization to the trial end (April 2, 2018) - up to 5 years
Number of Subjects With Aortic Stenosis	The first occurrence of clinically significant aortic stenosis	From randomization to the trial end (April 2, 2018) - up to 5 years
Number of Subjects With Atrial Fibrillation	The first occurrence of new or worsening of atrial fibrillation	From randomization to the trial end (April 2, 2018) - up to 5 years

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Paul Ridker, MD, MPH, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Cui J, Chasman DI, Raychaudhuri S, Xu C, Ridker PM, Solomon DH, Karlson EW. Genetics are not likely to offer clinically useful predictions for elevated liver enzyme levels in patients using low dose methotrexate. Semin Arthritis Rheum. 2022 Aug;55:152036. doi: 10.1016/j.semarthrit.2022.152036. Epub 2022 May 28.
• Reiss AB, Teboul I, Kasselman L, Ahmed S, Carsons SE, De Leon J. Methotrexate effects on adenosine receptor expression in peripheral monocytes of persons with type 2 diabetes and cardiovascular disease. J Investig Med. 2022 Aug;70(6):1433-1437. doi: 10.1136/jim-2022-002355. Epub 2022 May 23.
• Xu C, Selhub J, Jacques P, Paynter NP, MacFadyen JG, Glynn RJ, Ridker PM, Solomon DH. Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular inflammation reduction trial. Rheumatology (Oxford). 2021 Jun 18;60(6):2963-2968. doi: 10.1093/rheumatology/keaa650.
• Sparks JA, Dellaripa PF, Glynn RJ, Paynter NP, Xu C, Ridker PM, Solomon DH. Pulmonary Adverse Events in Patients Receiving Low-Dose Methotrexate in the Randomized, Double-Blind, Placebo-Controlled Cardiovascular Inflammation Reduction Trial. Arthritis Rheumatol. 2020 Dec;72(12):2065-2071. doi: 10.1002/art.41452. Epub 2020 Oct 7.
• Ridker PM, MacFadyen JG, Glynn RJ, Bradwin G, Hasan AA, Rifai N. Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial. Eur Heart J. 2020 Aug 14;41(31):2952-2961. doi: 10.1093/eurheartj/ehaa160.
• Solomon DH, Glynn RJ, Karlson EW, Lu F, Corrigan C, Colls J, Xu C, MacFadyen J, Barbhaiya M, Berliner N, Dellaripa PF, Everett BM, Pradhan AD, Hammond SP, Murray M, Rao DA, Ritter SY, Rutherford A, Sparks JA, Stratton J, Suh DH, Tedeschi SK, Vanni KMM, Paynter NP, Ridker PM. Adverse Effects of Low-Dose Methotrexate: A Randomized Trial. Ann Intern Med. 2020 Mar 17;172(6):369-380. doi: 10.7326/M19-3369. Epub 2020 Feb 18.
• Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, Mam V, Hasan A, Rosenberg Y, Iturriaga E, Gupta M, Tsigoulis M, Verma S, Clearfield M, Libby P, Goldhaber SZ, Seagle R, Ofori C, Saklayen M, Butman S, Singh N, Le May M, Bertrand O, Johnston J, Paynter NP, Glynn RJ; CIRT Investigators. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2019 Feb 21;380(8):752-762. doi: 10.1056/NEJMoa1809798. Epub 2018 Nov 10.
• Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM. Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis. Am Heart J. 2013 Aug;166(2):199-207.e15. doi: 10.1016/j.ahj.2013.03.018. Epub 2013 May 3.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): April 15, 2019
• Study Completion (Actual): October 30, 2019

Study Registration Dates

• First Submitted: May 1, 2012
• First Submitted That Met QC Criteria: May 7, 2012
• First Posted (Estimate): May 9, 2012

Study Record Updates

• Last Update Posted (Actual): July 24, 2020
• Last Update Submitted That Met QC Criteria: July 23, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Stroke; Metabolic Syndrome; Type 2 Diabetes; Myocardial Infarction; Cardiovascular death; Atherothrombosis; Cardiovascular Inflammation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate
• Other Study ID Numbers: 2012P-000857; U01HL101422 (U.S. NIH Grant/Contract); U01HL101389 (U.S. NIH Grant/Contract)