Trial DesignRationale and design of the Cardiovascular Inflammation Reduction Trial: A test of the inflammatory hypothesis of atherothrombosis
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,
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Clinical trial registration: ClinicalTrials.gov no. NCT01594333.