cardiovascular disease

CIRT Study Sheds Light on Anti-Inflammatory Mechanisms in CVD

Author:
Janet Wei, MD
Assistant professor of medicine, Barbra Streisand Women’s Heart Center at the Cedars-Sinai Smidt Heart Institute, Los Angeles

Citation: Wei J. CIRT Study Sheds Light on Anti-inflammatory Mechanisms in CVD. [Published online February 13, 2019]. Rheumatology Consultant.

Atherosclerotic cardiovascular events prevention has relied on the management of traditional risk factors such as hypertension, hypercholesterolemia, diabetes, and smoking. However, while statin therapy reduces cardiovascular events, many patients taking statins continue to experience events, described as a “residual risk” related to cholesterol, inflammation, or both. As reflected by elevated high-sensitivity C-reactive protein (hsCRP) level, inflammation is a predictor of future atherosclerotic cardiovascular events independent of conventional risk factors. Inflammation plays an important role in the development and progression of atherosclerosis, and atherosclerotic cardiovascular disease (CVD) is a major cause of mortality and morbidity in patients with chronic inflammatory conditions such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis.

A prior metanalysis found that patients with rheumatologic disease on methotrexate had a 21% lower risk of cardiovascular events compared to those on other disease-modifying anti-rheumatic drugs. Can reduction of inflammation prevent cardiovascular events? The Cardiovascular Inflammation Reduction Trial (CIRT) tested the inflammatory hypothesis by conducting a randomized double-blinded trial of low dose methotrexate in patients with prior myocardial infarction (MI) or multivessel coronary disease (CAD) who also had type 2 diabetes or the metabolic syndrome. After a median of 2.3 years, the trial was stopped for futility.

Researchers randomly assigned CIRT participants to low-dose methotrexate 15-20mg weekly or placebo. All participants received folic acid 1mg daily to reduce methotrexate side effects. Of the participants, the median age was 66 years, 19% were women, and 22% were nonwhite or Hispanic. The majority (86%) of patients were on a statin, and median low-density lipoprotein (LDL) cholesterol was well controlled at 68 mg/dL. Median hsCRP was 1.5 mg/L. For the 4786 patients randomized, methotrexate failed to reduce the risk of nonfatal MI, nonfatal stroke, or cardiovascular death (hazard ratio [HR], 1.01; 95% CI, 0.82-1.25) or other secondary endpoints at a median of 2.3 years (maximum 5 years). Methotrexate did not increase the risk of serious infection or bleeding, but it was associated with a higher incidence of mouth sores, oral pain, and non-basal cell skin cancers. 

 

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Although these findings were disappointing, this trial shed light regarding anti-inflammatory mechanisms in CVD. Methotrexate is a generic and inexpensive anti-inflammatory that has been used to treat rheumatoid arthritis and psoriasis. Its anti-inflammatory mechanisms involve adenosine-induced immunosuppression, anti-inflammatory cell proliferation and induction of apoptosis, and reduction of proinflammatory cytokines. Why did methotrexate fail to improve CVD outcomes in this trial? While methotrexate has been shown to reduce inflammatory biomarkers in patients with rheumatologic disease, methotrexate did not reduce interleukin-1β, interleukin-6, or hsCRP levels in patients with stable CAD in the CIRT trial. In addition, CIRT participants had relatively low hsCRP levels and thus were not a high “residual inflammatory risk” population.   

Unlike the CIRT trial, the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) demonstrated CVD event reduction in high-risk patients using canakinumab, an IL-1 inhibitor. CANTOS enrolled patients with elevated hsCRP of 2.0 mg/L or more and found that hsCRP levels decreased in a dose dependent fashion compared to placebo. With a mean follow-up of 3.7 years, the trial found that canakinumab 150mg every 3 months reduced major CVD events by 15% (HR, 0.85; 95% CI, 0.74-0.98). While canakinumab was associated with increases in neutropenia and fatal infection/sepsis in CANTOS, it was also associated with decreases in incident cancer, rheumatoid arthritis, osteoarthritis, and gout. However, the FDA did not approve canakinumab for the use of CVD prevention. 

Both CANTOS and CIRT study results have revealed that a more specific anti-inflammatory pathway or higher inflammatory risk population may be the key for CVD prevention. Previously in the Low-Dose Colchicine (LoDoCo) clinical trial, the anti-inflammatory colchicine was also tested for secondary CVDprevention but failed to reduce events in patients with established CAD already on optimal medical management. Currently, several clinical trials are underway for examining the effect of low-dose colchicine on major CVD events, including LoDoCo2 (Low-Dose Colchicine 2) in patients with stable CAD and the Colchicine Cardiovascular Outcomes Trial (COLCOT) in patients with MI.

Based on CIRT and CANTOS data, patients with baseline elevated hsCRP and subsequent reduction with anti-inflammatory agents are the ones who are likely to benefit with CVD risk reduction.

 

References:

  1. Cutollo M, Sulli A, Pizzorni C, Seriolo B. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60:729-735. http://dx.doi.org/10.1136/ard.60.8.729
  2. Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011;108:1362–70. https://www.ajconline.org/article/S0002-9149(11)02246-6/abstract.
  3. Nidorf SM, Eikelboom JW, Budgeon CA, Thompson PL. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol. 2013;61(4):404-410. https://doi.org/10.1016/j.jacc.2012.10.027.
  4. Ridker PM. How common is residual inflammatory risk? Circ Res. 2017;120(4):617-619. https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.116.310527.
  5. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events [published November 10, 2018]. N Engl J Med.  https://www.nejm.org/doi/full/10.1056/NEJMoa1809798.
  6. Ridker PM, Everett BM, Thuren T, et al.  Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119-1131. https://www.nejm.org/doi/full/10.1056/NEJMoa1707914.

 

For more on the CIRT study, visit Rheumatology Consultant.