Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial

Background Canakinumab, a monoclonal antibody targeting interleukin-1β, reduces inflammation and cardiovascular event rates with no effect on lipid concentrations. However, it is uncertain which patient groups benefit the most from treatment and whether reductions in the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) correlate with clinical benefits for individual patients. Methods The Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) used computer-generated codes to randomly allocate 10 061 men and women with a history of myocardial infarction to placebo or one of three doses of canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. In a prespecified secondary analysis designed to address the relationship of hsCRP reduction to event reduction in CANTOS, we evaluated the effects of canakinumab on rates of major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality according to on-treatment concentrations of hsCRP. We used multivariable modelling to adjust for baseline factors associated with achieved hsCRP and multiple sensitivity analyses to address the magnitude of residual confounding. The median follow-up was 3·7 years. The trial is registered with ClinicalTrials.gov, number NCT01327846. Findings Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0·75, 95% CI 0·66–0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0·90, 0·79–1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0·69, 95% CI 0·56–0·85, p=0·0004) and all-cause mortality (HRadj=0·69, 0·58–0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration. Interpretation The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab. Funding Novartis Pharmaceuticals.