Low-Dose Methotrexate for the Prevention of Atherosclerotic Events
Open accessAbstract
BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1β, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1β, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).
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In prior large trials (JUPITER, CIRT, CANTOS, SPIRE), placebo groups showed no substantive changes in LDL cholesterol, IL-1β, IL-6, or hsCRP over 3-5 years, and in STRENGTH (corn oil placebo) biomarker levels did not increase over time.
“No substantive biomarker changes were observed in the placebo groups over periods of 3 to 5 years for measures of LDL cholesterol, interleukin-1β, interleukin-6, or hsCRP in the large-scale JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin), CIRT (Cardiovascular Inflammation Reduction Trial), CANTOS (Canakinumab Anti-Inflammatory Thrombosis”
From Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy (2022) · cites this paper as [16]
The Cardiovascular Inflammation Reduction Trial (CIRT) yielded negative results.
“In another attempt to target inflammation, the Cardiovascular Inflammation Reduction Trial (CIRT)3 yielded negative, but highly educative results.”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [3]
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Cites
Nonparametric Estimation from Incomplete Observations
Kaplan, E. L., & Meier, P. (1992) · Springer series in statistics · doi:10.1007/978-1-4612-4380-9_25 · Cited by 45,232 · see citing works
Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
Ridker, P. M., Everett, B. M., Thuren, T., MacFadyen, J. G., Chang, W. H., Ballantyne, C., Fonseca, F., Nicolau, J., Koenig, W., Anker, S. D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1707914 · Cited by 9,482 · see citing works
Self-citationInflammation, Atherosclerosis, and Coronary Artery Disease
Hansson, G. K. (2005) · New England Journal of Medicine · doi:10.1056/nejmra043430 · Cited by 8,773 · see citing works
Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy
The AIM-HIGH Investigators (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1107579 · Cited by 2,911 · see citing works
Inflammation in Atherosclerosis
Libby, P., Ridker, P. M., & Hansson, G. K. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.09.009 · Cited by 2,228 · see citing works
Self-citationSaag, K. G., Teng, G. G., Patkar, N. M., Anuntiyo, J., Finney, C., Curtis, J. R., Paulus, H. E., Mudano, A. S., Pisu, M., Melton, M. E., et al. (2008) · Arthritis Care & Research · doi:10.1002/art.23721 · Cited by 1,452 · see citing works
Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study
Choi, H. K., Hernán, M. Á., Seeger, J. D., Robins, J. M., & Wolfe, F. (2002) · The Lancet · doi:10.1016/s0140-6736(02)08213-2 · Cited by 1,127 · see citing works
Pocock, S. J., Assmann, S. E., Enos, L. E., & Kasten, L. E. (2002) · Statistics in Medicine · doi:10.1002/sim.1296 · Cited by 1,077 · see citing works
Applying Cox Regression to Competing Risks
Lunn, M., & McNeil, D. (1995) · Biometrics · doi:10.2307/2532940 · Cited by 1,017 · see citing works
Ridker, P. M. (2016) · Circulation Research · doi:10.1161/circresaha.115.306656 · Cited by 1,002 · see citing works
Self-citationRidker, P. M., MacFadyen, J. G., Everett, B. M., Libby, P., Thuren, T. Y., Glynn, R. J., Ridker, P. M., MacFadyen, J. G., Everett, B. M., Libby, P., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32814-3 · Cited by 924 · see citing works
Self-citationEfficacy of Low-Dose Methotrexate in Rheumatoid Arthritis
Weinblatt, M. E., Coblyn, J. S., Fox, D. A., Fraser, P. A., Holdsworth, D. E., Glass, D. N., & Trentham, D. E. (1985) · New England Journal of Medicine · doi:10.1056/nejm198503283121303 · Cited by 872 · see citing works
Calculating the number needed to treat for trials where the outcome is time to an event
Altman, D. G., & Andersen, P. K. (1999) · BMJ · doi:10.1136/bmj.319.7223.1492 · Cited by 710 · see citing works
Cronstein, B. N., Naime, D., & Ostad, E. (1993) · Journal of Clinical Investigation · doi:10.1172/jci116884 · Cited by 683 · see citing works
The NLRP3 inflammasome in acute myocardial infarction
Toldo, S. A., & Abbate, A. (2017) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2017.161 · Cited by 673 · see citing works
Methotrexate in Resistant Juvenile Rheumatoid Arthritis
Giannini, E. H., Brewer, E. J., Kuzmina, N. N., et al. (1992) · New England Journal of Medicine · doi:10.1056/nejm199204163261602 · Cited by 593 · see citing works
Ridker, P. M., Libby, P., MacFadyen, J. G., Thuren, T. Y., Ballantyne, C. M., Fonseca, F. A. H., Köenig, W., Shimokawa, H., Everett, B. M., & Glynn, R. J. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy310 · Cited by 556 · see citing works
Self-citationSystematic Review and Meta-Analysis of Methotrexate Use and Risk of Cardiovascular Disease
Micha, R., Imamura, F., von Ballmoos, M. C. W., Solomon, D. H., Hernán, M. Á., Ridker, P. M., & Mozaffarian, D. (2011) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2011.06.054 · Cited by 535 · see citing works
Self-citationThe Asymptotic Properties of Nonparametric Tests for Comparing Survival Distributions
Schoenfeld, D. (1981) · Biometrika · doi:10.1093/biomet/68.1.316 · Cited by 505 · see citing works
Methotrexate—how does it really work?
Chan, E. S. L., & Cronstein, B. N. (2010) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2010.5 · Cited by 459 · see citing works
O’Donoghue, M. L., Braunwald, E., White, H. D., Steen, D. P., Lukas, M. A., Tarka, E., Steg, P. G., Hochman, J. S., Bode, C., Maggioni, A. P., et al. (2014) · JAMA · doi:10.1001/jama.2014.11061 · Cited by 456 · see citing works
Lachin, J. M., & Foulkes, M. A. (1986) · Biometrics · doi:10.2307/2531201 · Cited by 401 · see citing works
Glynn, R. J., & ROSNER, B. A. (2005) · American Journal of Epidemiology · doi:10.1093/aje/kwi309 · Cited by 380 · see citing works
Self-citationEverett, B. M., Pradhan, A. D., Solomon, D. H., Paynter, N., MacFadyen, J., Zaharris, E., Gupta, M., Clearfield, M., Libby, P., Hasan, A. A. K., et al. (2013) · American Heart Journal · doi:10.1016/j.ahj.2013.03.018 · Cited by 368 · see citing works
Self-citationWestlake, S. L., Colebatch, A. N., Baird, J., Kiely, P., Quinn, M., Choy, E., Ostor, A. J. K., & Edwards, C. J. (2010) · Rheumatology · doi:10.1093/rheumatology/kep366 · Cited by 357 · see citing works
Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin
Ridker, P. M. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw024 · Cited by 309 · see citing works
Self-citationO’Donoghue, M. L., Glaser, R., Cavender, M. A., Aylward, P. E., Bonaca, M. P., Budaj, A., Davies, R. Y., Dellborg, M., Fox, K. A. A., Gutierrez, J. A. T., et al. (2016) · JAMA · doi:10.1001/jama.2016.3609 · Cited by 249 · see citing works
Alten, R., Gómez-Reino, J. J., Durez, P., Beaulieu, A. D., Sebba, A. I., Krammer, G., Preiss, R., Arulmani, U., Widmer, A., Gitton, X., et al. (2011) · BMC Musculoskeletal Disorders · doi:10.1186/1471-2474-12-153 · Cited by 153 · see citing works
Computations for Group Sequential Boundaries Using the Lan-DeMets Spending Function Method
Reboussin, D. M., DeMets, D. L., Kim, K., & Lan, K. K. G. (2000) · Controlled Clinical Trials · doi:10.1016/s0197-2456(00)00057-x · Cited by 128 · see citing works
Solomon, D. H., Kremer, J. M., Fisher, M. C., et al. (2013) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2013.08.003 · Cited by 121 · see citing works
Self-citationBaylis, R. A., Gomez, D. A., Mallat, Z., Pasterkamp, G., & Owens, G. K. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.310097 · Cited by 92 · see citing works
CANTOS Trial Validates the Inflammatory Pathogenesis of Atherosclerosis
Weber, C., & von Hundelshausen, P. (2017) · Circulation Research · doi:10.1161/circresaha.117.311984 · Cited by 69 · see citing works
Krathen, M., Gottlieb, A. B., & Mease, P. J. (2010) · The Journal of Rheumatology · doi:10.3899/jrheum.100041 · Cited by 67 · see citing works
LANGE, E. L., Blizzard, L., Venn, A., et al. (2016) · Lara D. Veeken · doi:10.1093/rheumatology/kew214 · Cited by 59 · see citing works
Ibáñez, B., & Fuster, V. (2017) · Circulation Research · doi:10.1161/circresaha.117.312200 · Cited by 44 · see citing works
Adaptive Test for Testing the Difference in Survival Distributions
Pecková, M., & Fleming, T. (2003) · Lifetime Data Analysis · doi:10.1023/a:1025822717910 · Cited by 12 · see citing works
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Visseren, F. L. J., Mach, F., Smulders, Y. M., Carballo, D., Koskinas, K. C., Bäck, M., Benetos, A., Biffi, A., Boavida, J.-M., Capodanno, D., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab484 · Cited by 6,485 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.014 · Cited by 4,854 · see citing works
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Tardif, J.-C., Kouz, S., Waters, D. D., Bertrand, O. F., Diaz, R., Maggioni, A. P., Pinto, F. J., Ibrahim, R., Gamra, H., Kiwan, G. S., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1912388 · Cited by 3,159 · see citing works
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Virani, S. S., Newby, L. K., Arnold, S. V., Bittner, V., Brewer, L. C., Demeter, S. H., Dixon, D. L., Fearon, W. F., Hess, B., Johnson, H. M., et al. (2023) · Circulation · doi:10.1161/cir.0000000000001168 · Cited by 1,598 · see citing works
The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives
Tsalamandris, S., Antonopoulos, A. S., Oikonomou, E., Papamikroulis, G.-A., Vogiatzi, G., Papaioannou, S., Deftereos, S., & Tousoulis, D. (2019) · European Cardiology Review · doi:10.15420/ecr.2018.33.1 · Cited by 1,381 · see citing works
Single-cell immune landscape of human atherosclerotic plaques
Fernandez, D. M., Rahman, A. H., Fernandez, N. F., Chudnovskiy, A., Amir, E.-A. D., Amadori, L., Khan, N. S., Wong, C. K., Shamailova, R., Hill, C. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0590-4 · Cited by 970 · see citing works
Virani, S. S., Newby, L. K., Arnold, S. V., Bittner, V., Brewer, L. C., Demeter, S. H., Dixon, D. L., Fearon, W. F., Hess, B., Johnson, H. M., et al. (2023) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2023.04.003 · Cited by 596 · see citing works
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- Authors
- Ridker, P. M., Everett, B. M., Pradhan, A., MacFadyen, J. G., Solomon, D. H., Zaharris, E., Mam, V., Hasan, A., Rosenberg, Y., Iturriaga, E., Gupta, M., Tsigoulis, M., Verma, S., Clearfield, M., Libby, P., Goldhaber, S. Z., Seagle, R., Ofori, C., Saklayen, M., Butman, S., Singh, N., Le May, M., Bertrand, O., Johnston, J., Paynter, N. P., & Glynn, R. J.
- Affiliations
- Brigham and Women's Hospital (US)
- From 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...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-02-21
- Volume
- 380
- Issue
- 8
- Pages
- 752-762
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6587584
- OpenAlex
- W2899885364
- Cited by
- 1,317
- References
- 36
- Citations by year
- 2026: 113 · 2025: 141 · 2024: 141 · 2023: 153 · 2022: 171 · 2021: 197 · 2020: 231 · 2019: 160 · 2018: 9
- FWCI
- 64.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (UO1HL101422; UO1HL101389)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Antiplatelet Therapy and Cardiovascular Diseases
- Keywords
- methotrexate, low-dose methotrexate, atherosclerosis, cardiovascular events, inflammation, IL-1β, interleukin-6, C-reactive protein, type 2 diabetes, metabolic syndrome, myocardial infarction, stroke, cardiovascular mortality, unstable angina, folic acid, liver enzymes, skin cancer, drug safety, secondary prevention, stable coronary artery disease
- MeSH terms
- Aged, Transaminases, C-Reactive Protein, Cardiovascular Diseases, Coronary Artery Disease, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Follow-Up Studies, Humans, Immunosuppressive Agents, Male, Methotrexate, Middle Aged, Myocardial Infarction, Interleukin-6, Confidence Intervals, Proportional Hazards Models, Statistics, Nonparametric, Stroke, Metabolic Syndrome, Atherosclerosis, Interleukin-1beta
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