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Macrovascular Residual Risk Studies

5 November 2013
CIRT: Does targeting inflammation reduce residual cardiovascular risk?
Although inflammation plays an integral role in atherothrombosis, it is not known whether direct inhibition of inflammation will reduce the occurrence of cardiovascular events. The Cardiovascular Inflammation Reduction Trial (CIRT) will test the inflammatory hypothesis of atherothrombosis in patients with prior myocardial infarction (MI) and type 2 diabetes or metabolic syndrome.
Everett BM, Pradhan AD, Solomon DH, Paynter N, Macfadyen J, Zaharris E, Gupta M, Clearfield M, Libby P, Hasan AA, Glynn RJ, Ridker PM
Objective: Inflammation has a pivotal role in the atherothrombotic process, and recent insights from statin trials suggest that markers of subclinical inflammation can identify patients at increased cardiovascular risk. However, it has not been feasible to differentiate whether the clinical benefits of statin treatment are due to lipid effects, inhibition of inflammation or a combination of both processes. Therefore the CIRT trial was designed to test the hypothesis whether lowering inflammation will lower vascular event rates in patients at high cardiometabolic risk.
Study design: Randomized, double-blind, placebo-controlled, event-driven trial. The average follow-up period will be 3 to 5 years.
Study population: 7,000 patients aged at least 18 years and with prior MI (at least 60 days but no more than 5 years before screening), and either type 2 diabetes or the metabolic syndrome. Patients will continue on secondary prevention treatments including dual antiplatelet therapy, β-blockers, statins, angiotensin-converting enzyme inhibitors or receptor blockers, and anticoagulants.
Primary variable:

he primary variable is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death.

Secondary variables: 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

All patients will enter a 5- to 6-week (8-week maximum) open-label active run-in designed to exclude before randomization those patients initially intolerant of low-dose methotrexate. During this time methotrexate dosage will be increased from a weekly dose of 5 mg to the randomization target dose of 15 mg weekly. At the end of the run-in period, eligible patients who tolerate methotrexate will be randomized to weekly treatment with methotrexate or placebo. All patients will receive folic acid 1 mg to be taken on all days (Sunday-Friday) except the study treatment day (Saturday), when the weekly dose of methotrexate was given. Randomization will be stratified by time since MI (<6 months, ≥6 months), site, and the presence of either type 2 diabetes or the metabolic syndrome. Patients will be seen monthly for safety assessment for the first 6 months, and thereafter every 2 months. Patients who tolerate the study treatment 4 months after randomization will be up-titrated to the maximum dose of 20 mg weekly (or to matching placebo). Dosage can be adjusted depending on tolerability.

CIRT is an event-driven trial, designed to accrue 530 major cardiovascular events over an estimated average follow-up of 3 to 4 years. The trial has a 90% power to detect a 25% relative hazard reduction in the primary end point (2-sided log-rank test, α = 0.05). There is an additional 3-month washout period after trial completion and cessation of study treatment.

Authors’ conclusion: 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 reducing the residual risk of major cardiovascular events in high-risk patients receiving best evidence-based treatment.


Inflammation underlies the progression of atherosclerosis, culminating in clinical events. While epidemiological data show that measures of subclinical systemic vascular inflammation can identify patients at increased risk for cardiovascular events, and addition of such measures can improve risk stratification,1-4 no trial has been performed to investigate whether targeting inflammation, as sole intervention strategy, will reduce cardiovascular risk. However, insights from clinical trials suggest that statin therapy may have more beneficial effects in patients with baseline evidence of vascular inflammation.5,6 Indeed, in JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) in a primary prevention population, both the absolute risk and the absolute risk reduction with statin therapy were related to the level of C-reactive protein (CRP), and on-treatment levels of CRP and low-density lipoprotein cholesterol (LDL-C) were independently associated with residual risk.7,8 However, it is not possible to differentiate whether the clinical benefits observed in this trial were due to reduction in LDL-C alone, inhibition of inflammation, or both processes.

Given this rationale, the CIRT trial will evaluate whether low dose methotrexate will reduce the high residual risk of major vascular events in secondary prevention patients with either diabetes or metabolic syndrome. Low-dose methotrexate was selected as the study treatment, given that this agent has systemic anti-inflammatory effects without major impact on lipids or blood pressure, and is well tolerated with a reasonable safety profile.

Together with the results of the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), which is evaluating interleukin-1β (IL-1β) inhibition in patients with stable coronary artery disease and elevated high-sensitivity CRP (≥ 2 mg/L),9 these studies will provide important insights into the potential of targeting inflammation to reduce the high residual cardiovascular risk that persists despite best treatment efforts.

CIRT commenced in 2012, and results are anticipated by 2018.


1. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-43.
2. Koenig W, Lowel H, Baumert J, et al. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in Southern Germany. Circulation 2004;109:1349-53.
3. Kaptoge S, Di Angelantonio E, Lowe G, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 2010;375: 132-40.
4. Wilson PW, Pencina M, Jacques P, et al. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes 2008;1:92-7.
5. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1998;98:839-44.
6. Morrow DA, de Lemos JA, Sabatine MS, et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation 2006;114:281-8.
7. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.
8. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER Trial. Lancet 2009;373:1175-82.
9. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597-605.

Key words

Inflammation, residual cardiovascular risk; secondary prevention; atherosclerosis; methotrexate