Is it time to introduce anti-inflammatory drugs into secondary cardiovascular prevention: Evidence from clinical trials?

Abstract

A relationship between inflammatory activity, on the one hand, and haemostasias, cardiovascular risk factors and multiple phases of atherothrombotic diseases, on the other hand, has been documented for decades, but only recently have four large trials tested whether anti-inflammatory drugs could prevent major cardiovascular events (MACE) in > 25,000 patients followed on average for 1.9-3.7 years. In patients with recent myocardial infarction (MI) and serum C-reactive protein (CRP) ≥ 2 mg/L, the CANTOS trial showed that subcutaneous three-monthly 300 mg canakinumab [a high-cost, monoclonal antibody to interleukin (IL)-1β] reduced MACE versus placebo, but it increased fatal infections. In patients with recent MI (COLCOT trial) and in patients with chronic coronary syndromes (LoDoCo2 trial), oral 0.5 mg daily colchicine [a low-cost inhibitor of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing protein 3 (NLRP3) inflammasome] reduced MACE compared to placebo, with a small but significant increase in pneumonia (0.9% vs. 0.4% in COLCOT; not confirmed in LoDoCo2). In coronary artery disease patients with type 2 diabetes or metabolic syndrome, the CIRT trial found that oral 15-20 mg weekly methotrexate (an anti-rheumatic drug with multiple effects including inhibition of nuclear factor kB activity) compared to placebo did not reduce MACE, nor circulating IL-6 or CRP, while increasing the risk of non-basal cell skin cancer. Thus, three out of four large trials have now proven that drugs inhibiting the IL-1/IL-6 inflammatory axis can prevent MACE in patients with coronary artery disease. Colchicine, given its overall profile, is likely to become an integral part of secondary cardiovascular-disease prevention strategies.