CANTOS trial shows that specific inhibition of interleukin-1β leads to lower hsCRP levels and cardiovascular events in 1 and 4 years respectively. A group of 10,000 participants with established myocardial infarction and elevated hsCRP > 2 mg/L were randomized to receive canakinumab, a specific anti- IL1β monoclonal antibody, or placebo.
Cardiovascular benefits (17% event reduction) were seen with canakinumab 150 mg compared to control subjects, irrespective of lipid profile trends. Other significant clinical outcomes among patients receiving canakinumab were; more pseudo-membranous colitis (+233%), fatal infections and sepsis (+72%), leukopenia (+67%) and thrombocytopenia (+40%), but less fatal cancers (-30%), osteoarthritis (-28%) and gout (-53%); all consistent with the anti-inflammatory pathway of treatment.
The study supports the notion that vascular inflammation, in this case measured by IL1β-hsCRP axis, is a reversible contributor to atherosclerosis, independent of lipid measures. Participants' baseline LDL was 82 mg/dL, with no meaningful alterations during the course of the trial.
In the setting of unforeseen adverse events of pseudo-membranous colitis, fatal infections and sepsis, leukopenia and thrombocytopenia, I anticipate that more research would be needed to FDA approve canakinumab for secondary CVD prevention in adults with statin-residual atherosclerosis risk.
N E J M
Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved.
We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a hsCRP level of >2 mg/L.
The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.
At 48 months, the median reduction from baseline in the hsCRP level was 26% greater in the group that received the 50-mg dose of canakinumab, 37% greater in the 150-mg group, and 41% greater in the 300-mg group than in the placebo group.
Canakinumab did not reduce lipid levels from baseline.
At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.9 events per 100 person-years in the 300-mg group.
The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (p=0.30); in the 150-mg group, 0.85 (p=0.021); and in the 300-mg group, 0.86 (p=0.031).
ONLY the 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83, p=0.005).
Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94, p=0.31).
Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, INDEPENDENT of lipid-level lowering.
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Current pharmaceutical interventions that are designed to slow the progression of atherosclerosis focus almost exclusively on reducing plasma levels of cholesterol. However, clinical and experimental data support an additional critical role for inflammation in atherothrombosis. We previously found that downstream biomarkers of inflammation such as hsCRP and interleukin-6 are associated with an increased risk of cardiovascular events, independent of the cholesterol level. We have also found that statins reduce the levels of cholesterol and markers of inflammation, and in a series of clinical trials we and others subsequently found that beneficial outcomes after statin therapy relate to both a reduction in cholesterol level and inflammation inhibition. Yet, to date, no evidence has shown that reducing vascular inflammation in the absence of concomitant lipid lowering reduces the rates of cardiovascular events. As such, the inflammatory hypothesis of atherothrombosis has remained unproved.
Interleukin-1β is a cytokine that is central to the inflammatory response and that drives the interleukin-6 signaling pathway. Canakinumab, a fully human monoclonal antibody targeting interleukin-1β, has antiinflammatory effects and has been approved for clinical use in rheumatologic disorders. In a phase 2 trial involving patients with diabetes who were at high vascular risk, we found that interleukin-1β inhibition with canakinumab markedly reduced plasma levels of interleukin-6 and high-sensitivity C-reactive protein without lowering the level of low-density lipoprotein (LDL) cholesterol. Thus, we hypothesized that canakinumab could provide a critical proof-of-concept treatment to test the inflammatory hypothesis of atherothrombosis directly. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), a randomized, double-blind, placebo-controlled trial involving stable patients with previous myocardial infarction, evaluated whether canakinumab could prevent recurrent vascular events in men and women who have a persistent proinflammatory response, defined as a hsCRP > 2 mg/L.
CANTOS was designed to test directly the inflammatory hypothesis of atherothrombosis. In this trial, in patients with a history of myocardial infarction, the levels of hsCRP and IL-6 were significantly reduced from baseline by canakinumab, as compared with placebo, with no significant reduction in lipid levels from baseline. Although the 50-mg dose of canakinumab did not have a significant effect on the primary cardiovascular end point as compared with placebo, patients in the 150-mg group had a risk of the primary end point that was 15% lower than the risk in the placebo group and a risk of the key secondary cardiovascular end point that was 17% lower than that in the placebo group. The P values for both end points met the prespecified multiplicity-adjusted thresholds for statistical significance. Although the hazard ratios for the comparison of canakinumab with placebo in the 300-mg group were similar to those in the 150-mg group, the prespecified thresholds for significance were not met in this group. However, both a pooled analysis of all canakinumab doses and a trend analysis suggested a beneficial effect of canakinumab with regard to cardiovascular outcomes.
The specific targeting of interleukin-1β as a cytokine-based therapy for the secondary prevention of atherosclerotic events rests on several observations. The proinflammatory cytokine interleukin-1β plays multiple roles in the development of atherothrombotic plaque, including the induction of procoagulant activity, the promotion of monocyte and leukocyte adhesion to vascular endothelial cells, and the growth of vascular smooth-muscle cells.
The NOD-like receptor protein 3 (NLRP3) inflammasome activates interleukin-1β, a process promoted by cholesterol crystals, neutrophil extracellular traps, tissue hypoxia, and arterial flow patterns that are known to promote focal development of atherosclerosis within arteries. This activation of interleukin-1β stimulates the downstream interleukin-6 receptor signaling pathway, which has been implicated by mendelian randomization studies as a potential causal pathway for atherothrombosis. Furthermore, the expression of specific inflammasome gene modules affecting interleukin-1β has been associated with death from any cause and increased atherosclerosis in elderly patients.
Although the patients in CANTOS had generally well-controlled levels of LDL cholesterol, rates of both the primary end point and the secondary cardiovascular end point in the placebo group were high, with cumulative incidences of more than 20% at 5 years. Our data thus affirm that statin-treated patients with RESIDUAL inflammatory risk as assessed by means of a hsCRP > 2 mg/L at baseline have future event rates that are at least as high as, if not higher than, those among statin-treated patients with a residual risk due to LDL cholesterol level. These two groups of patients may differ and may require personalized approaches to treatment. Despite the fact that no significant reduction in cholesterol levels occurred in this trial, the magnitude of effect on cardiovascular events with canakinumab (given every 3 months) was similar to that associated with monoclonal antibodies targeting proprotein convertase subtilisin–kexin type 9 (PCSK9; given every 2 to 4 weeks).
Yet, inhibition of interleukin-1β is a narrowly focused intervention that represents only one of many potential antiinflammatory pathways that might serve as targets for atheroprotection. Thus, our data suggest that other antiinflammatory interventions, such as those that directly inhibit NLRP3 function or that alter downstream interleukin-6 signaling, may also be beneficial in reducing cardiovascular risk.
We found a significantly higher incidence of FATAL INFECTIONS and sepsis with canakinumab than with placebo, as well as a reduction in platelet counts with no increase in bleeding risk. By contrast, cancer mortality was significantly lower among patients assigned to receive canakinumab than among those in the placebo group, a finding that is consistent with experimental data relating interleukin-1 to the progression and invasiveness of certain tumors, particularly lung cancer. There was no significant difference between the canakinumab groups and the placebo group in all-cause mortality. No statistically or clinically significant hepatic toxic effect was noted. The beneficial effects of canakinumab that were observed with regard to arthritis, gout, and osteoarthritis are consistent with well-described effects of the interleukin-1 and interleukin-6 pathways in these disorders.
In conclusion, in CANTOS, patients with a history of myocardial infarction and hsCRP > 2 mg/L were randomly assigned to one of three doses of canakinumab or to placebo. Canakinumab significantly reduced hsCRP levels from baseline, as compared with placebo, without reducing the LDL cholesterol level, and the 150-mg dose resulted in a significantly lower incidence of recurrent cardiovascular events than placebo.