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Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease.

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  • 1. From the Center for Cardiovascular Disease Prevention (P.M.R., B.M.E., J.G.M., R.J.G.) and the Cardiovascular Division (P.M.R., B.M.E., P.L.), Brigham and Women's Hospital, Harvard Medical School, Boston; Novartis, East Hanover, NJ, and Basel, Switzerland (T.T., W.H.C.); Baylor College of Medicine, Houston (C.B.); Federal University of São Paulo (F.F.) and the Heart Institute (InCor), University of São Paulo Medical School (J.N.), São Paulo, and Faculdade Evangelica de Medicina do Parana, Curitiba (P.R.F.R.) - all in Brazil; Deutsches Herzzentrum München, Technische Universität München, German Center for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich (W.K.), and the Department of Cardiology and Berlin-Brandenburg Center for Regenerative Therapies, Charité Campus Virchow Klinikum, Universitätsmedizin Berlin, Berlin (S.D.A.) - both in Germany; Academic Medical Center of the University of Amsterdam, Amsterdam (J.J.P.K.), Alkmaar Medical Center, Alkmaar (J.H.C.), and VieCuri Medical Center for Northern Limburg, Venlo (R.P.T.T.) - all in the Netherlands; Manipal Hospital, St. John's Research Institute, Bangalore, India (P.P.); Pavol Jozef Safarik University, Kosice, Slovakia (D.P.); McGill University, Montreal (J.G.); First Faculty of Medicine and Thomayer Hospital, Prague, Czech Republic (R.C.); Cordoba Hospital, Cordoba, Argentina (A.L.); University of Szeged, Szeged, Hungary (T.F.); City Hospital No. 64, Medical Institute RUDN University, Moscow (Z.K.); Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania (L.V.-S.); University of East Anglia, Norwich Medical School, Norwich, United Kingdom (M.F.); Tohoku University Hospital, Sendai (H.S.), and National Cerebral and Cardiovascular Center, Osaka (H.O.) - both in Japan; and Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden (M.D.).
      Authors
    • Ridker PM 1
    • Everett BM 1
    • Thuren T 1
    • MacFadyen JG 1
    • Chang WH 1
    • Ballantyne C 1
    • Fonseca F 1
    • Nicolau J 1
    • Koenig W 1
    • Anker SD 1
    • Kastelein JJP 1
    • Cornel JH 1
    • Pais P 1
    • Pella D 1
    • Genest J 1
    • Cifkova R 1
    • Lorenzatti A 1
    • Forster T 1
    • Kobalava Z 1
    • Vida-Simiti L 1
    • Flather M 1
    • Shimokawa H 1
    • Ogawa H 1
    • Dellborg M 1
    • Rossi PRF 1
    • Troquay RPT 1
    • Libby P 1
    • Glynn RJ 1
    (28 authors)

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The New England Journal of Medicine, 27 Aug 2017, 377(12):1119-1131
https://doi.org/10.1056/nejmoa1707914 PMID: 28845751 

A comment on this article appears in "Effect size in CANTOS trial." BMJ Evid Based Med. 2018 Feb;23(1):44. A comment on this article appears in "Anti-inflammatory therapy with canakinumab for atherosclerotic disease: lessons from the CANTOS trial." J Thorac Dis. 2018 Feb;10 (2):695-698. A comment on this article appears in "Canakinumab for Atherosclerotic Disease." N Engl J Med. 2018 Jan 11;378(2):196-7. Show all (13)

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. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846 .).

Full text links 

Read article at publisher's site: https://doi.org/10.1056/nejmoa1707914

Read article for free, from open access legal sources, via Unpaywall: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1707914?articleTools=trueUnpaywall

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