Testing of C-reactive protein (CRP) may offer a quick and reliable way to identify the patients most likely to achieve the greatest benefits from long-term treatment with canakinumab (Novartis), according to a new analysis of the phase 3 CANTOS study.
The results, presented by Dr. Paul Ridker, MD, at the American Heart Association (AHA) Scientific Sessions 2017, were announced by Novartis and published simultaneously in The Lancet. The pre-planned secondary analysis of an exploratory endpoint showed that people with a prior heart attack who achieved high-sensitivity CRP (hsCRP) levels below 2 mg/L at three months after the first dose of canakinumab had a 25% reduction in major adverse cardiovascular events (MACE) versus placebo (adjusted hazard ratio [HRadj], 0.75, 95% confidence interval [CI], 0.66–0.85, P < 0.0001).
These patients also had a significant reduction of 31% in the rate of cardiovascular (CV) death (HRadj, 0.69, 95% CI, 0.56–0.85, P = 0.0004) and all-cause death (HRadj, 0.69, 95% CI, 0.58-0.81, P < 0.0001). There was no significant reduction in these endpoints observed among those treated with canakinumab who achieved hsCRP levels equal to or above 2 mg/L.
This analysis indicates that on-treatment hsCRP testing may offer a quick and reliable way to identify the patients most likely to achieve the greatest benefits from long-term canakinumab treatment. It also demonstrates that treating inflammation in addition to lowering cholesterol may significantly reduce the risk of recurrent CV events.
"This CANTOS analysis suggests that the initial biologic response to canakinumab may provide a simple method to identify which patients are most likely to obtain long-term benefits," said Dr. Ridker, CANTOS Study Chairman and Director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital. "Importantly, these data also support the value of targeting inflammation when treating patients who have had a heart attack in the past, reinforcing that 'lower is better' when it comes to levels of inflammation."
The analysis also evaluated the number of patients needed to treat (NNT). NNT is an epidemiological measure used to communicate the effectiveness of a health care intervention: the lower the NNT, the more effective the intervention. The estimated NNT of the subgroup of patients was 16, indicating that 16 patients treated with canakinumab whose hsCRP values dropped below 2 mg/L would need to be treated for five years to prevent one death, heart attack, stroke, or coronary revascularization. The NNT for the CANTOS cohort as a whole was 24.
Canakinumab has been shown to have major effects on inflammation, which is associated with atherothrombosis, the main cause of acute coronary syndromes and CV death. People with elevated inflammatory biomarkers, such as hsCRP, are at an increased risk of CV events. The hsCRP test is a simple, inexpensive, and widely available blood biomarker test that may also be used for residual inflammatory risk.
This subgroup analysis by Dr. Ridker included patients whose level of hsCRP at three months was 2 mg/L or greater, as well as those whose level was less than 2 mg/L, which is a commonly used clinical cut point for hsCRP measuring residual inflammatory risk. The analysis supports that patients who achieve an hsCRP level of less than 2 mg/L by the third month on treatment may receive the greatest benefit from long-term treatment with canakinumab.
The safety profile of canakinumab in the subgroup of patients whose hsCRP levels dropped below 2mg/L was consistent with the overall study population. The overall rates of adverse events (AEs), serious AEs, and discontinuations due to AEs in CANTOS were similar to placebo across all canakinumab doses. There was no relationship between on-treatment hsCRP levels and adverse events.
The six-year CANTOS study has enrolled more than 10,000 patients. As previously announced, initial data showed that quarterly treatment with 150 mg canakinumab resulted in a statistically significant 15% reduction in MACE—a composite of CV death, non-fatal myocardial infarction, and stroke—in people with a prior heart attack and inflammatory atherosclerosis.
Source: Novartis; November 13, 2017.