Adjunct canakinumab may modestly reduce the risk of major cardiovascular events in adults with a prior myocardial infarction and elevated CRP levels, but it may also increase the risk of fatal infection or sepsis
EBM Focus - Volume 12, Issue 36
- Inflammatory processes may contribute to the increased risk of major cardiovascular events in some patients with a history of myocardial infarction. The monoclonal antibody canakinumab targets interleukin-1 beta (IL-1 beta) and is FDA-approved for several conditions.
- In the recent CANTOS trial, 10,061 adults with a prior myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hs-CRP) levels were randomized to adjunct canakinumab 50 mg vs. 150 mg vs. 300 mg vs. placebo subcutaneous injection once every 3 months and followed for a median of 3.7 years.
- The rate of the first occurrence of a major cardiovascular event (nonfatal myocardial infarction, any nonfatal stroke, or cardiovascular death) was 3.86 per 100 person-years with canakinumab 150 mg vs. 4.5 with placebo (adjusted hazard ratio 0.85, 95% CI 0.74-0.98). The reduced rates with the other canakinumab doses did not reach statistical significance. Canakinumab was associated with increased risks of fatal infection or sepsis, leukopenia, thrombocytopenia, and pseudomembranous colitis.
- The modest benefit and adverse events with canakinumab do not support widespread changes in clinical practice, but this trial provides direct evidence that targeting inflammatory processes may reduce the risk of cardiovascular events in at-risk patients with signs of systemic inflammation.
Observational studies suggest that inflammatory processes may contribute to the increased risk of major cardiovascular events in some patients with a history of myocardial infarction (Circ Res 2016, Nat Rev Cardiol 2015). The recent CANTOS trial directly evaluated the efficacy of the fully human monoclonal antibody canakinumab, which targets the cytokine IL-1 beta and is FDA-approved for several conditions (FDA 2013 Sep), for preventing cardiovascular events in 10,061 adults (mean age 61 years, 74% men) with a prior MI ≥ 30 days before randomization and current hs-CRP levels ≥ 2 mg/L. All patients had pathologic findings of a healed or healing MI, and the vast majority were taking lipid-lowering agents (mostly statins), antithrombotic agents, anti-ischemic agents, and renin-angiotensin system inhibitors. The patients were randomized to 1 of 4 groups: canakinumab 50 mg vs. 150 mg vs. 300 mg vs. placebo subcutaneous injection once every 3 months with a median follow-up of 3.7 years. Exclusion criteria included ongoing use of other systemic anti-inflammatory agents, immunocompromised status, history of cancer other than basal-cell skin carcinoma, and MI resulting from percutaneous coronary intervention or coronary-artery bypass grafting. During enrollment, the target sample size was reduced from 17,200 to 10,000 patients, and follow-up was extended by 1 year to maintain the target number of events. The primary outcome was the first occurrence of a major cardiovascular event (nonfatal myocardial infarction, any nonfatal stroke, or cardiovascular death).
The rate of the primary outcome per 100 person-years was 3.86 with canakinumab 150 mg vs. 4.5 with placebo (adjusted hazard ratio [HR] 0.85, 95% CI 0.74-0.98). Canakinumab 300 mg had a similarly reduced rate (adjusted HR 0.86, 95% CI 0.75-0.99) but did not reach statistical significance after adjustments for multiple comparisons and other factors, and the 50 mg dose did not appear to have an effect (adjusted HR 0.93, 95% CI 0.8-1.07). Consistent results were seen for the single outcomes of MI or any coronary revascularization, but no significant differences between the canakinumab groups and placebo were observed for the single outcomes of stroke, cardiovascular death, or all-cause mortality. Regarding biomarkers of interest in this population, canakinumab was associated with significantly reduced hs-CRP levels and increased triglyceride levels, but not significantly changed low- or high-density lipoprotein levels. Canakinumab was associated with a significantly increased risk of some adverse events including fatal infection or sepsis (0.31 vs. 0.18 events per 100 person-years, p = 0.02), leukopenia, thrombocytopenia, and pseudomembranous colitis, and a reduced risk of others including fatal cancer (0.45 vs. 0.64, p = 0.02).
This trial demonstrated that canakinumab may modestly reduce the risk of major cardiovascular events, particularly MI, in adults with a previous MI and current elevated hs-CRP levels. The 95% confidence interval in risk reduction includes differences that may not be clinically important, and the reduced risk was statistically significant only for the 150 mg dose. The modest and uncertain benefit should be weighed against the increased risk of fatal infection and other adverse events when considering canakinumab. The reduced risk of fatal cancer is unexpected and is reported on in detail elsewhere (Lancet 2017). This study included patients with elevated hs-CRP levels, but CRP is a non-specific marker of increased inflammation and its use may have resulted in the inclusion of patients unlikely to benefit from canakinumab.
Overall, the results of this trial do not support widespread changes in clinical practice, but they are important because they provide direct evidence that targeting inflammatory processes may reduce the risk of cardiovascular events in at-risk patients with signs of systemic inflammation. Additional studies with canakinumab and other anti-inflammatory therapies (such as methotrexate, being evaluated in the ongoing CIRT trial, Am Heart J 2013) are necessary to clarify their efficacy and clinical indications for their use.