While inflammation contributes crucially to atherothrombosis and patients with elevated levels of the inflammatory biomarker hsCRP have increased vascular risk, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the proposed 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 recurrent myocardial infarction, stroke, and cardiovascular death among patients with stable cardiovascular disease who are at increased risk indicated by persistent elevations of hsCRP. The investigators propose to conduct a randomized, double-blind, placebo-controlled, multi-center trial among 7,000 men and women with prior myocardial infarction and hsCRP>2mg/L and <20mg/L. Eligible participants will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM (initial dose 10 mg po per week with a safety-based titration to 15 mg po per week after 4 months based on evidence of safety and tolerability). Study participants will additionally receive 1 mg daily oral folate. Although widely considered safe in contemporary practice settings, LDM complications will further be minimized by mandatory bi-annual education programs for all investigators and coordinators, through weekly telephone communication with all study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, or other methotrexate risk factors, by conducting an initial 4-week active-therapy run-in designed to eliminate individuals intolerant to treatment before randomization, and through monthly monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose reductions 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 will include non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death, with additional monitoring for all-cause mortality. Secondary endpoints include diabetes, venous thrombosis, and atrial fibrillation, all of which have an inflammatory basis. The study team assembled has extensive experience in the design, initiation, conduct, and analysis of large-scale randomized trials and in the clinical use of LDM. Our external rheumatology consultants all feel the dose of LDM is safe for this post-MI population and that LDM is free of the confounding effects on lipids, glucose, and thrombosis that significantly limit other agents including hydroxychloroquine. The potential clinical impact of this trial 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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Clinical Trials Review Committee (CLTR)
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Hasan, Ahmed AK
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Brigham and Women's Hospital
United States
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Ridker, Paul M (2017) How Common Is Residual Inflammatory Risk? Circ Res 120:617-619
Sparks, Jeffrey A; Barbhaiya, Medha; Karlson, Elizabeth W et al. (2017) Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study. Semin Arthritis Rheum 47:133-142
Goldfine, Allison B; Shoelson, Steven E (2017) Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk. J Clin Invest 127:83-93
Ridker, Paul M (2016) A Test in Context: High-Sensitivity C-Reactive Protein. J Am Coll Cardiol 67:712-723
Ridker, Paul M (2016) From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection. Circ Res 118:145-56
Brown, W Virgil; Remaley, Alan T; Ridker, Paul M (2015) JCL Roundtable: is inflammation a future target in preventing arteriosclerotic cardiovascular disease. J Clin Lipidol 9:119-28
Piazza, Gregory; Ridker, Paul M (2015) Is venous thromboembolism a chronic inflammatory disease? Clin Chem 61:313-6
Kim, Seoyoung C; Schneeweiss, Sebastian; Glynn, Robert J et al. (2015) Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study. Ann Rheum Dis 74:1968-75
Ridker, Paul M (2014) Targeting inflammatory pathways for the treatment of cardiovascular disease. Eur Heart J 35:540-3
Ridker, Paul M; L├╝scher, Thomas F (2014) Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 35:1782-91

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