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