Rationale and design of the Cardiovascular Inflammation Reduction Trial: a test of the inflammatory hypothesis of atherothrombosis

Abstract

Background: Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known.

Design: The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.govNCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants.

Summary: CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.

Copyright © 2013 Mosby, Inc. All rights reserved.

Figures

Figure 1

Simplified flow diagram of the Cardiovascular Inflammation Reduction Trial (CIRT). Clinically stable patients with a history of myocardial infarction in the past 5 years and either type 2 diabetes or the metabolic syndrome will enter a 5 to 6 week active run-in period with escalating doses of methotrexate (advancing from 5 mg/week to 15 mg/week). Those who tolerate the run-in and have no new laboratory abnormalities will then be randomized to active methotrexate or placebo and followed for an average period of 3 to 4 years. The primary endpoint is the occurrence of myocardial recurrent infarction, stroke, of cardiovascular death. All safety evaluations except visit 2.5 consist of a safety laboratory evaluation and either a telephone or an in-person visit to ascertain medication side effects, adverse events, and any key clinical endpoints. Visit 2.5 is a telephone visit without laboratory assessment. M5-M10-M15-M20 indicates variable dose of active methotrexate with a target dose of 15–20 mg per week. P5-P10-P15-P20 indicates variable dosing of methotrexate placebo. The maximum dose of methotrexate is 15 mg/week until 4 months after randomization, when the dose can be increased to 20 mg/week. Abbreviations: Eval, evaluation; MI, myocardial infarction; MTX, methotrexate; T2DM, type 2 diabetes mellitus; VN, visit N (a representative follow-up visit); VF, final visit.

Figure 2

Schematic representation of the study drug titration algorithm. A. Flow diagram for changes in study drug dose. Using information gathered from routine questionnaires and regular safety laboratory studies, the dose of study drug can be increased, maintained, decreased, and stopped (temporarily or permanently). Sham dose changes in the placebo arm maintain the study blind. B. Matrix of routine safety laboratory values and current study drug dose used in the drug titration algorithm.

Figure 2

Schematic representation of the study drug titration algorithm. A. Flow diagram for changes in study drug dose. Using information gathered from routine questionnaires and regular safety laboratory studies, the dose of study drug can be increased, maintained, decreased, and stopped (temporarily or permanently). Sham dose changes in the placebo arm maintain the study blind. B. Matrix of routine safety laboratory values and current study drug dose used in the drug titration algorithm.