Overview of anti-inflammatory therapy for ischemic heart disease

For the past ~10 medical management involves certain pillars of therapy including: Statins, anti-platelets, ACE inhibitors and anti-ischemic therapy (beta-blockers/calcium channel blockers). However, recently there has been an interest and increase in experimental evidence of the use of targeted anti-inflammatory therapy for stable ischemic heart disease. Here I will briefly review some of the recent evidence regarding this practice. 

CANTOS Trial, NEJM 2017

The CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study), published in NEJM 2017, randomized 10,061 patients with previous MI AND CRP level >2mg/L to three different doses of Canakinumab (50mg, 150mg and 300mg q3months) or placebo. Canakinumab is a human monoclonal antibody that issued in rheumatologic disorders by targeting interleukin-1β. The primary endpoint was a composite endpoint of non-fatal MI, non-fatal, stroke, or cardiovascular death. At 48 months all three groups receiving Canakinumab experienced a reduction in their CRP levels in a dose-dependent response. There was a significant reduction in the hazard ratio for the primary outcome in the 150 mg group compared to the placebo group, but not in the 50 mg group or 300mg group. It was concluded that Canakinumab at a dose of 150 mg every three months lead to a significantly lower rate of recurrent cardiovascular events and compared to placebo. 

CIRT Trial, NEJM 2019 

The CIRT trial (cardiovascular inflammation reduction trial) published in NEJM 2019 randomized 4786 patients with a previous history of MI or multivessel coronary disease and additionally had either type 2 diabetes, or the presence of metabolic syndrome, to low-dose methotrexate (15 to 20 mg weekly) or placebo. The primary end-point was also a composite outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The trial stopped after immediate follow up of 2.3 years and the hazard ratio for the primary outcome between the methotrexate group and the control group was 0.96, (confidence interval: 0.79- 1.16). It was concluded that in stable atherosclerotic coronary disease, low-dose methotrexate did not reduce cardiovascular events more than placebo. 

LoDoCo2 Trial, NEJM 2020

In the LoDoCo 2 trail (low-dose colchicine), a total of 5522 patients were randomized to either low-dose colchicine (0.5 mg per day) or placebo. The primary endpoint was a composite end point of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The hazard-ratio for the primary endpoint was 0.69 (confidence interval, 0.57 to 0.83) which favoured the low-dose colchicine group. It was concluded that the risk of cardiovascular events were significantly lower along those who received 0.5 mg of Colchicine once daily than those who received placebo. 

Figure 1. Cumulative Incidence of the Primary End Point and the Key Secondary End Point in the LoDoCo2 trial

Summary

The initial Cantos trial first provide evidence that inflammation plays a causal role in the pathogenesis coronary atherosclerotic disease and interventions to reduce this burden of inflammation may also reduce cardiovascular events. The results from the recent trial specifically the LoDoCa trial supports that daily therapy of low dose Colchicine may actually be of benefit when added to other secondary therapies to reduce future cardiovascular events in these patients.

References

Nidorf, Stefan M., Aernoud TL Fiolet, Arend Mosterd, John W. Eikelboom, Astrid Schut, Tjerk SJ Opstal, Salem HK The et al. "Colchicine in patients with chronic coronary disease." New England journal of medicine 383, no. 19 (2020): 1838-1847.

Ridker, Paul M., Brendan M. Everett, Tom Thuren, Jean G. MacFadyen, William H. Chang, Christie Ballantyne, Francisco Fonseca et al. "Antiinflammatory therapy with canakinumab for atherosclerotic disease." New England journal of medicine377, no. 12 (2017): 1119-1131.

Ridker, Paul M., Brendan M. Everett, Aruna Pradhan, Jean G. MacFadyen, Daniel H. Solomon, Elaine Zaharris, Virak Mam et al. "Low-dose methotrexate for the prevention of atherosclerotic events." New England Journal of Medicine380, no. 8 (2019): 752-762.

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