Elsevier

American Heart Journal

Volume 166, Issue 2, August 2013, Pages 199-207.e15
American Heart Journal

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

https://doi.org/10.1016/j.ahj.2013.03.018Get rights and content

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.gov NCT01594333) 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.

Section snippets

Epidemiologic and basic evidence for inflammation in cardiovascular disease

Inflammation plays a pivotal role in the development and progression of atherosclerosis.1 Both innate and acquired immunity play key roles in inflammatory cell adhesion and transmigration across the endothelium, fatty streak formation, smooth muscle migration, plaque progression, and ultimately lesion rupture and thrombosis. The clinical consequences of this process include myocardial infarction (MI), stroke, and cardiovascular death.

Numerous epidemiologic studies support a key role for

Clinical evidence that treating inflammation matters

To date, no clinical trial has directly addressed whether targeting inflammation alone will reduce cardiovascular risk. A number of clinical trials in both primary and secondary prevention, however, indicate that such an approach may be promising.

As first noted in the CARE trial more than a decade ago, the benefits of pravastatin were particularly pronounced among patients with evidence of ongoing vascular inflammation.9 The AFCAPS/TexCAPS trial of lovastatin yielded similar results.10 The

Type 2 diabetes, metabolic syndrome, and inflammation

Approximately 30% to 40% of patients with acute coronary syndromes have diabetes or metabolic syndrome, many diagnosed with these dysmetabolic states the time of their presentation.15, 16 Post-MI patients with type 2 diabetes or the metabolic syndrome have an increased risk of recurrent cardiovascular events, including MI, stroke, and cardiovascular death. In the MIRACL, WIZARD, and TNT trials, patients with metabolic syndrome had a 33% to 44% increased risk of recurrent cardiovascular events.17

Methotrexate and cardiovascular disease: epidemiology and molecular mechanisms

Directly testing the inflammatory hypothesis of atherothrombosis requires an agent that has systemic anti-inflammatory effects without substantive impact on lipids or blood pressure. The agent must also be well tolerated and have a reasonable safety profile. Low-dose methotrexate (LDM) has these characteristics.

Low-dose methotrexate (dose range 10-30 mg/wk) is widely used as first-line treatment for patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis. Because of the wide use

CIRT: a direct test of the inflammatory hypothesis of atherothrombosis

The CIRT's primary objective is to determine whether anti-inflammatory therapy with LDM (target dose 15-20 mg/wk) as compared with placebo will reduce the rate of recurrent cardiovascular events among patients with prior MI and either type 2 diabetes or the metabolic syndrome. The primary trial end point, the composite of nonfatal MI, nonfatal stroke, and cardiovascular death, will be adjudicated by an independent Clinical Events Committee (CEC) blinded to study treatment allocation. Secondary

Trial sponsorship and organization

CIRT is funded by the National Heart Lung and Blood Institute (NHLBI) through a U01 mechanism to Dr Paul Ridker (HL101422), the trial principal investigator, and to Dr Robert J. Glynn (HL101389) who is the Director of the Data Coordinating Center. Drs Ridker and Glynn conduct all trial activities at Brigham and Women's Hospital and Harvard Medical School in Boston, MA.

TEVA, Inc, is supplying active methotrexate (Trexall 5 mg), and Amneal Pharmaceuticals, Inc, is supplying active folic acid

Conclusion

Inflammation mediates the effects of many risk factors on arterial biology and thus drives atherothrombosis. Although considerable evidence suggests that reducing inflammation leads to improved cardiovascular outcomes, no study has yet tested whether directly targeting inflammation will reduce the occurrence of heart attack, stroke, and cardiovascular death. By using LDM, an effective systemic anti-inflammatory medication without known effects on traditional determinants of cardiovascular risk,

References (48)

  • W. Koenig 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)
  • S. Kaptoge et al.

    C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis

    Lancet

    (2010)
  • P.M. Ridker et al.

    Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score

    JAMA

    (2007)
  • P.W. Wilson et al.

    C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study

    Circ Cardiovasc Qual Outcomes

    (2008)
  • P.M. Ridker 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)
  • P.M. Ridker et al.

    Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events

    N Engl J Med

    (2001)
  • P.M. Ridker et al.

    Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein

    N Engl J Med

    (2008)
  • D.A. Morrow 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)
  • M. Zeller et al.

    Prevalence and impact of metabolic syndrome on hospital outcomes in acute myocardial infarction

    Arch Intern Med

    (2005)
  • N.M. Boyer et al.

    Trends in clinical, demographic, and biochemical characteristics of patients with acute myocardial infarction from 2003 to 2008: a report from the American Heart Association Get with the Guidelines Coronary Artery Disease Program

    J Am Heart Assoc

    (2012)
  • G.G. Schwartz et al.

    Relation of characteristics of metabolic syndrome to short-term prognosis and effects of intensive statin therapy after acute coronary syndrome: an analysis of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial

    Diabetes Care

    (2005)
  • R.B. Goldberg et al.

    Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) Trial. The Care Investigators

    Circulation

    (1998)
  • A. Keech et al.

    Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial

    Diabetes Care

    (2003)
  • H.N. Ginsberg et al.

    Effects of combination lipid therapy in type 2 diabetes mellitus

    N Engl J Med

    (2010)
  • Cited by (0)

    Clinical trial registration: ClinicalTrials.gov no. NCT01594333.

    View full text