Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

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Abstract

BACKGROUND Experimental and clinical data suggest that reducing inflammation without affecting lipidlevels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis ofatherothrombosis has remained unproved.METHODSWe conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonalantibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarctionand a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trialcompared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneouslyevery 3 months) with placebo. The primary efficacy end point was nonfatalmyocardial infarction, nonfatal stroke, or cardiovascular death.RESULTSAt 48 months, the median reduction from baseline in the high-sensitivity C-reactive proteinlevel 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 the300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline.At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 eventsper 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group,3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years inthe 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mggroup, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P=0.30); in the 150-mg group, 0.85 (95%CI, 0.74 to 0.98; P=0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P=0.031). The150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold forstatistical significance for the primary end point and the secondary end point that additionallyincluded hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs.placebo, 0.83; 95% CI, 0.73 to 0.95; P=0.005). Canakinumab was associated with a higher incidenceof fatal infection than was placebo. There was no significant difference in all-cause mortality(hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P=0.31).CONCLUSIONSAntiinflammatory therapy targeting the interleukin-1β innate immunity pathway withcanakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrentcardiovascular events than placebo, independent of lipid-level lowering. (Funded byNovartis; CANTOS ClinicalTrials.gov number, NCT01327846.)
Lingua originaleEnglish
pagine (da-a)1119-1131
Numero di pagine13
RivistaNew England Journal of Medicine
Volume377
Stato di pubblicazionePublished - 2017

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