@article{215656cae5594d9a9b9407b7de46ab5a,
title = "Antiinflammatory therapy with canakinumab for atherosclerotic disease",
abstract = "BACKGROUND: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. METHODS: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level 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 the 300-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 events per 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 in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 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). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included 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 incidence of 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). CONCLUSIONS: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering.",
author = "{CANTOS Trial Group} and Ridker, {P. M.} and Everett, {B. M.} and T. Thuren and MacFadyen, {J. G.} and Chang, {W. H.} and C. Ballantyne and F. Fonseca and J. Nicolau and W. Koenig and Anker, {S. D.} and Kastelein, {J. J.P.} and Cornel, {J. H.} and P. Pais and D. Pella and J. Genest and R. Cifkova and A. Lorenzatti and T. Forster and Z. Kobalava and L. Vida-Simiti and M. Flather and H. Shimokawa and H. Ogawa and M. Dellborg and Rossi, {P. R.F.} and Troquay, {R. P.T.} and P. Libby and Glynn, {R. J.} and H. Krum and J. Varigos and P. Siostrzonek and P. Sinnaeve and N. Gotcheva and H. Yong and M. Urina-Triana and D. Milicic and R. Vettus and Manolis, {A. J.} and F. Wyss and A. Sigurdsson and A. Fucili and I. Veze and B. Petrauskiene and L. Salvador and Klemsdal, {T. O.} and F. Medina and A. Budaj and P. Otasevic and M. Lainscak and Seung, {K. B.} and P. Commerford and M. Donath and Hwang, {J. J.} and H. Kultursay and S. Bilazarian and C. East and L. Forgosh and B. Harris and M. Ligueros and E. Bohula and B. Charmarthi and S. Cheng and S. Chou and J. Danik and G. McMahon and B. Maron and M. Ning and B. Olenchock and R. Pande and T. Perlstein and A. Pradhan and N. Rost and A. Singhal and V. Taqueti and N. Wei and H. Burris and A. Cioffi and Dalseg, {A. M.} and N. Ghosh and J. Gralow and T. Mayer and H. Rugo and V. Fowler and Limaye, {A. P.} and S. Cosgrove and D. Levine and R. Lopes and J. Scott and R. Hilkert and G. Tamesby and C. Mickel and B. Manning and J. Woelcke and M. Tan and S. Manfreda and T. Ponce and J. Kam and R. Saini and K. Banker and T. Salko and P. Nandy and R. Tawfik and G. O{\textquoteright}Neil and S. Manne and P. Jirvankar and S. Lal and D. Nema and J. Jose and R. Collins and K. Bailey and R. Blumenthal and H. Colhoun and B. Gersh and M. Abreu and Actis, {M. V.} and J. Aiub and F. Aiub and J. Albisu and A. Alvarisqueta and V. Avalos and M. Barreto and Berli, {M. A.} and C. Blumberg and M. Bocanera and C. Botta and L. Bowen and N. Budassi and S. Buhlman and Westberg, {J. C.} and T. Carabajal and G. Caruso and J. Casala and G. Cendali and G. Coloma and Berra, {F. C.} and C. Cuneo and N. Degennaro and M. Dellasa and M. Diaz and {Dos Santos}, P. and V. Espinosa and A. Facello and M. Facello and E. Farias and Fernandez, {A. A.} and V. Ferrari and Pacora, {F. F.} and Flores, {G. S.} and M. Franco and A. Gabito and Viola, {H. G.} and F. Garcia and {Garcia Duran}, R. and {Garcia Pinna}, J. and J. Glenny and {Godoy Sanchez}, M. and A. Grosse and P. Guzman and E. Hasbani and M. Hominal and J. Iba{\~n}ez and H. Jure and D. Jure and Vico, {M. L.} and G. Liniado and H. Luciardi and H. Luquez and G. Maehara and L. Maffei and C. Majul and M. Mallagray and S. Marinaro and J. Martinez and R. Massaccesi and {De Los Milagros Had}, M. and Azize, {G. M.} and O. Montana and E. Montenegro and Y. Morell and J. Muntaner and S. Navarrete and M. Olmedo and M. Paganini and S. Paz and {Perez Manghi}, F. and D. Piskorz and C. Polato and R. Recoaro and A. Romano and M. Salinger and A. Sanchez and Saravia, {M. A.} and R. Sarjanovich and G. Scaro and Schiavi, {L. B.} and J. Soler and V. Tinnirello and A. Tomassi and M. Valle and J. Mcgill",
note = "Funding Information: This investigator-driven clinical trial was sponsored by Novartis. The trial protocol, available with the full text of this article at NEJM.org, was designed by academic members of the executive committee with input from physician and statistician employees of the sponsor. The protocol was approved at participating centers by the responsible institutional review board or ethics committee, as applicable in the 39 countries involved. An independent data and safety monitoring committee oversaw the trial. The sponsor was responsible for data collection. The first author and an academic statistician at Brigham and Women{\textquoteright}s Hospital had full access to the trial databases, generated trial analyses, prepared the first draft of the manuscript, and made the decision to submit the manuscript for publication. The authors assume responsibility for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol. Publisher Copyright: Copyright {\textcopyright} 2017 Massachusetts Medical Society.",
year = "2017",
month = sep,
day = "21",
doi = "10.1056/NEJMoa1707914",
language = "English",
volume = "377",
pages = "1119--1131",
journal = "New England Journal of Medicine",
issn = "0028-4793",
number = "12",
}