Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease
List of authors.
A complete list of members of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) Trial Group is provided in the Supplementary Appendix, available at NEJM.org.
Abstract
Background
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.
Methods
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 high-sensitivity C-reactive protein level of 2 mg or more per liter. 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.
Results
At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points 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 3.90 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 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). 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; 95% CI, 0.73 to 0.95; 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; 95% CI, 0.83 to 1.06; P=0.31).
Conclusions
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. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.)
Methods
Trial Design and Oversight
This investigator-driven clinical trial was sponsored by Novartis. The trial protocol, available with the full text of this article at NEJM.org, was designed by academic members of the executive committee with input from physician and statistician employees of the sponsor. The protocol was approved at participating centers by the responsible institutional review board or ethics committee, as applicable in the 39 countries involved. An independent data and safety monitoring committee oversaw the trial. The sponsor was responsible for data collection. The first author and an academic statistician at Brigham and Women’s Hospital had full access to the trial databases, generated trial analyses, prepared the first draft of the manuscript, and made the decision to submit the manuscript for publication. The authors assume responsibility for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol.
Trial Population
Patients were eligible for enrollment if they had a history of myocardial infarction and had a blood level of high-sensitivity C-reactive protein of 2 mg or more per liter despite the use of aggressive secondary prevention strategies. The trial excluded from enrollment patients with a history of chronic or recurrent infection, previous cancer other than basal-cell skin carcinoma, a suspected or known immunocompromised state, a history or high risk of tuberculosis or disease related to the human immunodeficiency virus, or ongoing use of other systemic antiinflammatory treatments. Details of the inclusion and exclusion criteria are provided in Section B in the Supplementary Appendix, available at NEJM.org.
Randomization
Initially, patients were randomly assigned in a 1:1:1 ratio to receive placebo, canakinumab at a dose of 150 mg, or canakinumab at a dose of 300 mg. After the enrollment of 741 patients, a 50-mg dose of canakinumab was added at the request of a regulatory agency, and the randomization ratio was adjusted accordingly; we sought to achieve a final randomization ratio of 1.5 (placebo group):1:1:1 (Section C in the Supplementary Appendix). All doses of canakinumab and placebo were administered subcutaneously once every 3 months; for the 300-mg dose, the regimen was 300 mg every 2 weeks for the first two doses, then once every 3 months. Randomization was performed with the use of a centralized computer system, with stratification according to the time since the index myocardial infarction and according to trial part (before vs. after inclusion of the 50-mg dose group).
End Points
The primary efficacy end point was the first occurrence of nonfatal myocardial infarction, any nonfatal stroke, or cardiovascular death in a time-to-event analysis. The trial had two key secondary efficacy end points. The first key secondary end point included the components of the primary end point as well as hospitalization for unstable angina that led to urgent revascularization. The second key secondary end point, the incidence of new-onset type 2 diabetes among patients with prediabetes at randomization in a time-to-event analysis, is not reported here. The two other prespecified secondary end points were death from any cause and the composite of nonfatal myocardial infarction, any nonfatal stroke, or death from any cause. All the components of these end points were adjudicated by an end-point adjudication committee, whose members were unaware of the trial-group assignments.
Statistical Analysis
The trial was designed to accrue a total of 1400 primary end-point events across all the groups. Assuming that all three active doses would result in a primary event rate that was 20% lower than the rate with placebo, we calculated that the trial would have more than 90% power to detect a significantly lower risk with at least one canakinumab dose than with placebo. The investigators initially sought to enroll 17,200 patients in order to accrue 1400 events over a period of 5 years. In December 2013, at the request of the sponsor, the sample size was reduced to 10,000 patients. The planned follow-up was extended by 1 year to maintain the targeted number of events.
The distributions of the percentage change from baseline in the high-sensitivity C-reactive protein and lipid levels were compared between the placebo group and each canakinumab group at intervals up to 48 months. Similar comparisons were made for interleukin-6 levels up to 12 months. Log-rank tests and Cox proportional-hazards models, stratified according to the time since the index myocardial infarction and according to trial part, were used to analyze the prespecified primary and key secondary cardiovascular end points that occurred during trial follow-up, according to the intention-to-treat principle.
The formal evaluation of significance for individual doses, with adjustment for multiple comparisons, followed a closed testing procedure (Section C in the Supplementary Appendix). On the basis of the closed testing procedure, and with the use of the prespecified allocation of alpha error, the two-sided P value thresholds for statistical significance for the primary end point were 0.01058 for the test of the 300-mg dose of canakinumab versus placebo and 0.02115 for the tests of the other two doses versus placebo. The closed testing procedure also specified that formal significance testing for the key secondary end points would be performed for any given dose only if the significance threshold for the primary end point for that dose had been met.
Although the primary analysis strategy was based on pairwise comparisons of individual dose groups with the placebo group, comparisons were also made between the incidence rates in the placebo group and the incidence rates across the ascending canakinumab doses (using scores of 0, 1, 3, and 6 that were proportional to doses in a trend analysis) and in the combined canakinumab groups versus placebo. In addition, analyses that focused on patients who adhered to the trial regimen were performed, with follow-up for each patient being censored 119 days after the last injection was received. The significance thresholds for these tests were not adjusted for multiple comparisons. Similar analyses were used for adverse events. All P values are two-sided, and all confidence intervals were computed at the 95% level.
Results
Patients
Trial enrollment began in April 2011 and was completed in March 2014; the last trial visit was in June 2017. Of 17,482 patients who had previously had myocardial infarction and had undergone screening in the central laboratory, 10,061 (57.6%) underwent randomization correctly and received at least one dose of canakinumab or placebo (Fig. S1 in the Supplementary Appendix). The most common reasons for exclusion were a high-sensitivity C-reactive protein level of less than 2 mg per liter (46.0% of the excluded patients), active tuberculosis or tuberculosis risk factors (25.4%), and exclusionary concomitant disorders (9.9%).
Table 1.
Table 1. Characteristics of the Trial Participants.The mean age of the participants who underwent randomization was 61 years, 25.7% of the patients were women, and 40.0% had diabetes (Table 1). Most participants had undergone previous revascularization procedures (66.7% of the patients had undergone percutaneous coronary intervention, and 14.0% coronary-artery bypass grafting). At baseline, antithrombotic agents were taken by 95.0% of the patients, lipid-lowering agents by 93.4%, anti-ischemia agents by 91.4%, and inhibitors of the renin–angiotensin system by 79.7%. The median high-sensitivity C-reactive protein level at trial entry was 4.20 mg per liter, and the median LDL cholesterol level was 82.4 mg per deciliter (2.13 mmol per liter).
Effects on Inflammatory Biomarkers and Lipid Levels
Figure 1.
Figure 1. Effects of Canakinumab, as Compared with Placebo, on Plasma Levels of High-Sensitivity C-Reactive Protein, Low-Density Lipoprotein (LDL) Cholesterol, High-Density Lipoprotein (HDL) Cholesterol, and Triglycerides.Shown are the median percentage changes from baseline (dashed line). Specific data points, as well as data regarding interleukin-6 levels at 3 months and 12 months, are presented in Tables S1 through S5 in the Supplementary Appendix.
At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group (P<0.001 for all comparisons of the median percentage change in a canakinumab group with the placebo group) (Figure 1, and Fig. S2 and Tables S1 through S5 in the Supplementary Appendix). Similar effects were observed for the interleukin-6 level (measured up to 12 months). By contrast, canakinumab use resulted in no significant reduction from baseline in the LDL cholesterol or HDL cholesterol level and in a 4 to 5% median increase in the triglyceride level.
Follow-up and Effects on Clinical End Points
Table 2.
Table 2. Incidence Rates and Hazard Ratios for Major Clinical Outcomes and All-Cause Mortality.Figure 2. 
Figure 2. Cumulative Incidence of the Primary End Point and the Key Secondary Cardiovascular End Point.Shown is the cumulative incidence of the primary end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death in the placebo group versus the various canakinumab dose groups (Panels A through C). The insets show the same data on an enlarged y axis. The threshold P value for the primary end point was 0.02115 in the 150-mg group and 0.01058 in the 300-mg group. The group receiving the 150-mg dose of canakinumab met the prespecified multiplicity-adjusted threshold for statistical significance for the primary cardiovascular end point and for the key secondary cardiovascular end point that additionally included hospitalization for unstable angina that led to urgent revascularization (Panel D). The threshold P value for the key secondary cardiovascular end point in the 150-mg group was 0.00529.
By the end of follow-up, 18.1% of patients in the placebo group had discontinued the trial regimen, as compared with 18.7% of patients in the combined canakinumab groups (Fig. S1 in the Supplementary Appendix). At a median follow-up of 3.7 years, the incidence rate for the primary end point (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the group that received the 50-mg dose of canakinumab, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group (Table 2). No significant effect, as compared with placebo, was observed with regard to the primary end point in the 50-mg group (hazard ratio, 0.93; P=0.30) (Figure 2A). By contrast, a significant effect for the primary end point was observed in the 150-mg group (hazard ratio vs. placebo, 0.85; P=0.02075, with a threshold P value of 0.02115) (Figure 2B). In the 300-mg group, the hazard ratio was similar to that in the 150-mg group, but the P value did not meet the prespecified threshold for significance (hazard ratio vs. placebo, 0.86; P=0.0314, with a threshold P value of 0.01058) (Figure 2C). The P value for trend across the canakinumab dose groups as compared with the placebo group was 0.02, and the P value for the comparison of all canakinumab doses combined with the placebo group was 0.02 (both results not adjusted for multiple testing).
For the key secondary cardiovascular end point (the components of the primary end point plus hospitalization for unstable angina that led to urgent revascularization), the incidence rate was 5.13 events per 100 person-years in the placebo group, 4.56 events per 100 person-years in the group that received the 50-mg dose of canakinumab, 4.29 events per 100 person-years in the 150-mg group, and 4.25 events per 100 person-years in the 300-mg group (Table 2). In the group that received the 150-mg dose of canakinumab (for which the P value met the significance threshold for the primary end point), the hazard ratio versus placebo for the secondary cardiovascular end point was 0.83 (P=0.00525, with a threshold P value of 0.00529) (Figure 2D). According to the closed testing procedure, formal significance testing for the prespecified secondary end point was not performed for the 50-mg group and the 300-mg group. The hazard ratio versus placebo in the 50-mg group was 0.90, and the hazard ratio versus placebo in the 300-mg group was 0.83 (Figs. S3 and S4 in the Supplementary Appendix). The P value for trend across the canakinumab groups as compared with the placebo group was 0.003, and the P value for the comparison of all canakinumab doses combined with the placebo group was 0.001 (both results not adjusted for multiple testing).
Analyses of the additional secondary end points and of the components of the primary and secondary end points were not adjusted for multiple testing (Table 2). Nominally significantly lower rates than in the placebo group were seen with regard to myocardial infarction in the group that received the 150-mg dose of canakinumab; with regard to hospitalization for unstable angina that led to urgent revascularization in the 150-mg group and the 300-mg group; and with regard to any coronary revascularization in all three dose groups. All-cause mortality was neutral in the comparison of all canakinumab doses with placebo (hazard ratio, 0.94; 95% confidence interval, 0.83 to 1.06; P=0.31).
In analyses that focused on patients who adhered to the trial regimen, the observed hazard ratios were 1.00 in the placebo group, 0.90 in the group that received the 50-mg dose of canakinumab, 0.83 in the 150-mg group, and 0.79 in the 300-mg group (P=0.003 for trend across groups). In similar analyses for the key secondary cardiovascular end point, the corresponding hazard ratios were 1.00, 0.88, 0.80, and 0.77 (P<0.001 for trend across groups).
Adverse Events and Other Clinical Outcomes
Table 3.
Table 3. Incidence Rates and Numbers of Serious Adverse Events and Selected Safety Laboratory Data During Treatment, Stratified According to Trial Group.Neutropenia was more common among patients who were assigned to receive canakinumab than among those in the placebo group, and significantly more deaths were attributed to infection or sepsis in the pooled canakinumab groups than in the placebo group (incidence rate, 0.31 vs. 0.18 events per 100 person-years; P=0.02) (Table 3). The patients who died from infection tended to be older and more likely to have diabetes than those who did not die from infection. Six confirmed cases of tuberculosis occurred during the trial, with similar rates in the pooled canakinumab group and the placebo group (0.06% in each group); five cases occurred in India and one in Taiwan.
Thrombocytopenia was more common among patients who were assigned to receive canakinumab than among those in the placebo group, but no significant difference in the incidence of hemorrhage was observed. The incidence rate of injection-site reaction did not differ significantly between any canakinumab group and the placebo group. In a finding that was consistent with known effects of interleukin-1β inhibition, canakinumab resulted in significantly fewer reports of arthritis, gout, and osteoarthritis than did placebo (Table 3). Cancer mortality was significantly lower with canakinumab than with placebo.16
Discussion
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 high-sensitivity C-reactive protein and interleukin-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 (3.86 vs. 4.50 events per 100 person-years) and a risk of the key secondary cardiovascular end point that was 17% lower than that in the placebo group (4.29 vs. 5.13 events per 100 person-years). 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.17-19 In mice, interleukin-1β deficiency reduces lesion formation, whereas in cholesterol-fed pigs, exposure to exogenous interleukin-1β increases intimal medial thickening.20,21 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.22-25 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.26,27 More recently, studies in parabiotic mice28 and studies of clonal hematopoiesis29,30 have implicated interleukin-1β in processes by which bone marrow activation accelerates atherosclerosis. 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.31
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 high-sensitivity C-reactive protein level of 2 mg or more per liter 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.32 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).33,34 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.35-37 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 infection 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.16,38,39 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 a high-sensitivity C-reactive protein level of 2 mg or more per liter were randomly assigned to one of three doses of canakinumab or to placebo. Canakinumab significantly reduced high-sensitivity C-reactive protein 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.
Supplementary Material
References (39)
1. Ross R. Atherosclerosis — an inflammatory disease. N Engl J Med 1999;340:115-126
2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-1695
3. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol 2009;54:2129-2138
4. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-979
5. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 2000;342:836-843
6. Ridker PM, Rifai N, Pfeffer MA, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998;98:839-844
7. Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001;344:1959-1965
8. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29-38
9. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20-28
10. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207
11. Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of dual low-density lipoprotein cholesterol and high-sensitivity C-reactive protein targets more frequent with the addition of ezetimibe to simvastatin and associated with better outcomes in IMPROVE-IT. Circulation 2015;132:1224-1233
12. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009;360:2416-2425
13. Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med 2012;367:2396-2406
14. Ridker PM, Howard CP, Walter V, et al. Effects of interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012;126:2739-2748
15. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597-605
16. Ridker PM, MacFadyen JG, Thuren T, Everett B, Libby P, Glynn RJ. Effects of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind placebo-controlled trial. Lancet (in press).
17. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 2011;117:3720-3732
18. Dinarello CA, Simon A, van der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11:633-652
19. Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, Dinarello CA. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol 1986;124:179-185
20. Kirii H, Niwa T, Yamada Y, et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2003;23:656-660
21. Shimokawa H, Ito A, Fukumoto Y, et al. Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo: the role of platelet-derived growth factor. J Clin Invest 1996;97:769-776
22. Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010;464:1357-1361
23. Rajamäki K, Lappalainen J, Oörni K, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 2010;5:e11765-e11765
24. Xiao H, Lu M, Lin TY, et al. Sterol regulatory element binding protein 2 activation of NLRP3 inflammasome in endothelium mediates hemodynamic-induced atherosclerosis susceptibility. Circulation 2013;128:632-642
25. Folco EJ, Sukhova GK, Quillard T, Libby P. Moderate hypoxia potentiates interleukin-1β production in activated human macrophages. Circ Res 2014;115:875-883
26. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379:1214-1224
27. IL6R Genetics Consortium Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012;379:1205-1213
28. Sager HB, Heidt T, Hulsmans M, et al. Targeting interleukin-1β reduces leukocyte production after acute myocardial infarction. Circulation 2015;132:1880-1890
29. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 2017;355:842-847
30. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med 2017;377:111-121
31. Furman D, Chang J, Lartigue L, et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med 2017;23:174-184
32. Ridker PM. Residual inflammatory risk: addressing the obverse side of the atherosclerosis prevention coin. Eur Heart J 2016;37:1720-1722
33. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-1722
34. Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527-1539
35. Morton AC, Rothman AMK, Greenwood JP, et al. The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study. Eur Heart J 2015;36:377-384
36. Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation 2013;128:1910-1923
37. Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 2014;35:1782-1791
38. Apte RN, Dotan S, Elkabets M, et al. The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev 2006;25:387-408
39. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140:883-899
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Figures/Media
- Table 1. Characteristics of the Trial Participants.
Table 1. Characteristics of the Trial Participants. - Figure 1. Effects of Canakinumab, as Compared with Placebo, on Plasma Levels of High-Sensitivity C-Reactive Protein, Low-Density Lipoprotein (LDL) Cholesterol, High-Density Lipoprotein (HDL) Cholesterol, and Triglycerides.
Figure 1. Effects of Canakinumab, as Compared with Placebo, on Plasma Levels of High-Sensitivity C-Reactive Protein, Low-Density Lipoprotein (LDL) Cholesterol, High-Density Lipoprotein (HDL) Cholesterol, and Triglycerides. Shown are the median percentage changes from baseline (dashed line). Specific data points, as well as data regarding interleukin-6 levels at 3 months and 12 months, are presented in Tables S1 through S5 in the Supplementary Appendix.
- Table 2. Incidence Rates and Hazard Ratios for Major Clinical Outcomes and All-Cause Mortality.
Table 2. Incidence Rates and Hazard Ratios for Major Clinical Outcomes and All-Cause Mortality. - Figure 2. Cumulative Incidence of the Primary End Point and the Key Secondary Cardiovascular End Point.
Figure 2. Cumulative Incidence of the Primary End Point and the Key Secondary Cardiovascular End Point. Shown is the cumulative incidence of the primary end point of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death in the placebo group versus the various canakinumab dose groups (Panels A through C). The insets show the same data on an enlarged y axis. The threshold P value for the primary end point was 0.02115 in the 150-mg group and 0.01058 in the 300-mg group. The group receiving the 150-mg dose of canakinumab met the prespecified multiplicity-adjusted threshold for statistical significance for the primary cardiovascular end point and for the key secondary cardiovascular end point that additionally included hospitalization for unstable angina that led to urgent revascularization (Panel D). The threshold P value for the key secondary cardiovascular end point in the 150-mg group was 0.00529.
- Table 3. Incidence Rates and Numbers of Serious Adverse Events and Selected Safety Laboratory Data During Treatment, Stratified According to Trial Group.
Table 3. Incidence Rates and Numbers of Serious Adverse Events and Selected Safety Laboratory Data During Treatment, Stratified According to Trial Group.
