Inflammation as potential target for therapy to target residual risk post ACS
After treatment with high-intensity statins, patients can still have residual cholesterol risk or residual inflammatory risk. This means that patients still have either high levels of LDL-c, but normal high sensitivity C-reactive protein (hsCRP) or normal LDL-c but high hsCRP. Both patient groups need additional care to reduce LDL-c levels or inflammatory burden.
Ridker recently reported on the impact of residual inflammation. He showed a continuous positive linear association between hsCRP levels and relative risk of future events. The question now is, whether lowering these levels would also result in a lower CV risk. This seems plausible, as it has been demonstrated that the magnitude of independent risk associated with inflammation is at least as large, if not larger, than that of blood pressure and cholesterol. Furthermore, lowering LDL-c as well as hsCRP using statin monotherapy or statins plus ezetimibe in the PROVE-IT and IMPROVE-IT studies, significantly improved the frequency of recurrent vascular events1,2.
“The magnitude of independent risk associated with inflammation is at least as large, if not larger, than that of blood pressure and cholesterol.”
These data support the idea of additional CV benefit when inhibiting inflammatory pathways specifically, for example by targeting IL-1 and IL-6 pathways. Main downstream targets of these pathways are fibrinogen and CRP and indeed, individuals with low CRP levels due to polymorphisms in genes involved in the IL-6 pathway, have a lower risk of coronary heart disease3,4.
Two on-going trials currently investigate whether specific reduction of inflammation reduces CV event rates. One of these trials is the ‘cardiovascular inflammation reduction trial’ (CIRT), in which low doses of methotrexate are used. The idea of using methotrexate (MTX) is distilled from an observation in rheumatoid arthritis patients. MTX-treated patients have reduced CV event rates5. Moreover, cholesterol-fed rabbits that were given MTX showed less evidence of cholesterol plaque in the arteries compared to control rabbits. In the CIRT trial, 7000 patients on statins, ACE/ARBs, BB, ASA are being enrolled that have evidence of inflammation, diabetes or metabolic syndrome. Patients are randomised to 15-52 mg MTX once a week or placebo, for 3 years and will be evaluated for non-fatal myocardial infarction (MI), non-fatal stroke or CV death.
The other trial is the event-rate driven ‘canakinumab anti-inflammatory thrombosis outcomes study’ (CANTOS), which is now fully enrolled (10.064 patients) and will be read out within the next 12 months. Patients on statins, ACE/ARBs, BB, ASA and with persistent elevation of hsCRP were given a monoclonal IL-1β antibody, canakinumab, which neutralises the bioactivity of this pro-inflammatory cytokine. The phase II study of this antibody already demonstrated that IL-6, hsCRP and fibrinogen were lowered when canakinumab was administered every 3 months6. CANTOS investigates whether the non-fatal MI, non-fatal stroke and CV event rate will be reduced in patients randomised to 50, 150 or 300 mg canakinumab every 3 months or placebo.
Other on-going studies with regard to anti-inflammatory regimes include the LODOKO trial in which colchicine reduced secondary CV disease. This regime is now being repeated by multiple groups around the world. Unfortunately, not all anti-inflammatory drugs give the desired effect; the losmapimod MAP-kinase inhibitor did not result in reduced cardiovascular CV outcomes in patients with prior acute MI7.
More work needs to be done to increase survival of ACS patients. In this respect, Ridker emphasised that in addition to the residual cholesterol and inflammatory risk, residual triglyceride risk is another interesting area of research that can take this issue forward and should be elaborated on.