Anti-inflammatory canakinumab reduces CV risk independent of lipid lowering
The anti-inflammatory agent canakinumab is found to reduce the risk of cardiovascular (CV) events in high-risk patients, providing proof of concept that inhibiting inflammation can improve CV outcomes independent of cholesterol levels.
The findings came from the CANTOS study (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which compared CV outcomes of three doses of canakinumab (50 mg, 150 mg and 300 mg) with placebo in patients with previous MI and elevated levels (≥2 mg/L) of the inflammatory marker high-sensitivity C-reactive protein (hsCRP) but low LDL-cholesterol levels. [N Engl J Med 2017, doi: 10.1056/NEJMoa1707914]
“For the first time, we definitively showed that lowering inflammation independent of cholesterol levels reduces CV risk,” said principal investigator Professor Paul Ridker of Harvard Medical School, Boston, Massachusetts, US. “Our findings may represent the endgame of more than 2 decades of research, stemming from the observation that half of heart attacks occur in people who do not have high cholesterol levels.”
The CANTOS investigators randomized 10,061 patients to receive placebo or canakinumab 50 mg, 150 mg or 300 mg every 3 months. The primary endpoint was major adverse CV event (MACE) comprising nonfatal MI, nonfatal stroke and CV death, while the secondary endpoint was MACE or hospitalization for unstable angina requiring urgent revascularization. Patients in all arms had low median LDL-cholesterol levels (81.2–83.5 mg/dL) and high median hsCRP levels (4.1–4.2 mg/dL) at baseline.
At 48 months, hsCRP levels were reduced by a median of 26 percent, 37 percent and 41 percent with canakinumab 50 mg, 150 mg and 300 mg, respectively, compared with placebo.
“The primary endpoint was reduced by 15 percent with canakinumab 150 mg [incidence rate, 4.5 vs 3.9 per 100 person-years; hazard ratio [HR], 0.85; p=0.021] and 14 percent with canakinumab 300 mg [incidence rate, 4.5 vs 3.9 per 100 person-years; HR, 0.86; p=0.031] vs placebo. The secondary endpoint was reduced by 17 percent with canakinumab 150 mg and 300 mg,” reported Ridker. “Due to multiplicity testing, only the 150 mg dose of canakinumab formally met statistical significance for both primary and secondary endpoints.”
“Notably, the secondary endpoint was reduced by 27 percent among patients with above median reduction in hsCRP at 3 months [HR, 0.73; p=0.0001]. In contrast, the CV risk in patients with below median hsCRP reduction at 3 months was comparable to that in the placebo group [HR, 0.95; p=0.47],” he continued. “This finding may help identify patients who may benefit from treatment with canakinumab.”
“Leukopenia and fatal infection were more commonly reported in patients receiving canakinumab vs placebo, suggesting that patients receiving canakinumab should be monitored for early signs of infection,” reported Ridker.
“Our study suggests that statin-treated patients with residual inflammatory risk, as opposed to those with residual cholesterol risk, may be managed differently,” he advised.
Interestingly, the study also showed significant reductions in cancer mortality (HR, 0.49; p=0.0009), lung cancer incidence (HR, 0.33; p=0.00008) and lung cancer mortality (HR, 0.23; p=0.0002) with canakinumab 300 mg vs placebo. [Lancet 2017, doi: 10.1016/S0140-6736(17)32247-X]