By Juan Carlos Kaski*, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA, FRSM
Atherogenesis is an inflammatory process in its own right. Rapid coronary artery disease progression and plaque disruption are associated with vascular and systemic inflammation. Moreover, inflammation has been also shown to be a key mechanism underlying coronary microvascular dysfunction leading to microvascular angina. Patients suffering from chronic inflammatory conditions, particularly those triggered by autoimmune mechanisms, are at a higher risk of coronary artery disease and cardiovascular events.
C-reactive protein has been postulated to be a marker of both inflammation and coronary artery disease and disease progression. Although anti-inflammatory interventions should in theory improve cardiovascular outcomes, drugs such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAID) have been shown to be potentially harmful in the context of the acute coronary syndrome. Colchicine, on the contrary, has been effective in patients with stable coronary artery disease, albeit in studies involving small numbers of patients. The Low-Dose Colchicine (LoDoCo) study,1 which tested this anti-inflammatory agent for the secondary prevention of cardiovascular events in 532 patients, resulted in significant beneficial cardiovascular effects, but with a high rate of gastrointestinal side effects. Colchicine is currently being assessed in a large study of patients with stable coronary artery disease (NCT02551094).
A monoclonal antibody (canakinumab) targeting interleukin-1β resulted in significant beneficial effects, as shown by the CANTOS study.2 Patients included in CANTOS were high-risk secondary prevention patients, who despite being on high-intensity statin therapy, continued to have elevated CRP levels. Of interest, cancer mortality -particularly lung cancer – was significantly lower in patients treated with canakinumab vs. placebo. Importantly, however, there was a significantly increased risk of death with canakinumab caused by infection or sepsis, compared with events in the placebo arm (0.31 vs 0.18 events per 100 patient years; P = 0.02). Neutropenia and thrombocytopenia were more common in patients treated with canakinumab.
The Cardiovascular Inflammation Reduction Trial (CIRT), recently published in the New England Journal of Medicine,3 showed that methotrexate had no beneficial effects on cardiovascular outcomes or on interleukin-1β, interleukin-6, or C-reactive protein (CRP) levels in patients with ischaemic heart disease. In CIRT, patients with previous MI or multivessel coronary artery disease in addition to type 2 diabetes or metabolic syndrome were randomized to receive low-dose methotrexate (15-20 mg) or matching placebo. The trial was stopped by the Data and Safety Monitoring Board for futility after a median of 2.3 years. From an objective perspective, despite the overwhelming data supporting the role of inflammation in atherogenesis, treatment strategies have so far been rather disappointing with the exception of canakinumab in CANTOS -a proof of concept study- which showed a small benefit on clinical outcomes and a significant increase in risk of death mainly associated with sepsis. Methotrexate treatment, in CIRT, was “neutral” regarding cardiac events but there were significantly more adverse events with methotrexate, compared with placebo and a higher incidence of non-basal-cell skin cancers. Colchicine is currently being tested in a large study.
From an optimistic perspective, the inflammation hypothesis remains viable, particularly the interleukin-1β to interleukin-6 pathway, as supported by vascular biology research and the CANTOS results. The cost of potentially effective treatments (i.e. monoclonal antibodies), however, is extremely high and this will limit their use in clinical practice. Although at present there is little data that support therapeutic strategies for IHD based on anti-inflammatory agents, scientists, clinicians and trialists should be encouraged to continue the search for suitable pharmacological therapies able to effectively tackle pro-inflammatory mechanisms to reduce cardiovascular events. Caution, however, is necessary when interpreting available treatment data and when designing future studies in order that truly meaningful data can be gathered, with true translational impact.
Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA, FRSM
Professor of Cardiovascular Science
St George’s, University of London
- Nidorf SM, Eikelboom JW, Budgeon CA et al. Low-dose colchicine for secondary prevention of cardiovascular disease. J Am Coll Cardiol 2013; 61:404–10
- Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab of atherosclerotic disease. N Engl J Med 2017; 377:1119-1131
- Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019; 380:752-762