The Cardiovascular Inflammation Reduction Trial (CIRT) is an NHLBI funded trial (U01 HL 101422) that will examine the effects of low dose methotrexate (LDM) on secondary prevention of cardiovascular (CV) events in a high-risk post-MI population without systemic rheumatic disease. The hypothesis underlying this trial relates to the inflammatory underpinnings of CV disease and whether suppression of inflammation with LDM can reduce recurrent CV events. LDM has been in widespread use for several decades for rheumatic diseases, but most of the toxicity warnings and monitoring guidelines are based on data from relatively small trials and observational datasets not designed to study drug safety. We propose to study adverse events (AE) including hepatic injury, pneumonitis, hematologic deficiencies, infection, nausea, stomatitis and rash among 7,000 post- MI subjects randomized to LDM or placebo in CIRT. Our team has substantial expertise pharmacoepidemiology, genetics and predictive modeling.
Specific Aims are 1) To estimate the incidence rate and relative risk of LDM AEs, including hepatic, pulmonary, hematologic, infectious, and mucocutaneous;2) To study sociodemographic, lifestyle, anthropometric, co-morbidities, co-medications, genetic, and methotrexate metabolites as predictors of LDM AEs;and 3) To develop and test various risk prediction rules for LDM AEs. We will use our epidemiologic expertise to build comprehensive models that include clinical variables, drug metabolites, genetic predictors and drug exposure that can be used to personalized targeted therapy. The discovery and clinical use of markers associated with a greater likelihood of AE from LDM would provide an important public health benefit to rheumatic disease patients and potentially to a large population from the general population if the CIRT trial shows reduction on cardiovascular events with LDM.

Public Health Relevance

Low dose methotrexate (LDM) is widely used and is expected to grow in prescriptions. The discovery and clinical use of markers associated with a greater likelihood of AE from LDM would provide an important public health benefit to many patients. Genotypic and methotrexate metabolite data will provide unique information for this application and others associated with CIRT.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL119718-01A1
Application #
8760929
Study Section
Clinical Trials Review Committee (CLTR)
Program Officer
Iturriaga, Erin
Project Start
2014-08-15
Project End
2019-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$693,860
Indirect Cost
$240,207
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115