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N Engl J Med. 2019 Feb 21;380(8):720-728. doi: 10.1056/NEJMoa1814630.

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

Collaborators (218)

Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH, Crawford J, Neaton J, Francis CW, Prins M, Ten Cate-Hoek A, Ten Cate H, Shad-Small S, Lambert C, Machiels G, Efira A, Martens M, Dirix L, Rolfo C, Forget F, Wynendaele W, Denardin da Rosa V, Massayuki Imanishi W, Michels de Oliveira M, Pires L, Silva Melo Cruz FJ, Borges G, Zukin M, Pedrini JL, Zago Campos C, Altino J, Roberte Adam Van Eyll BMH, Brust L, Hegg R, Ramacciotti E, Ribeiro Villaca P, Mazzoleni F, Grabarz D, Keyserlingk J, Cournoyer G, Yeo E, Buchler T, Klenha K, Melichar B, Prausova J, Smakal M, Smakalova J, Sochor M, Weiner P, Prosecky R, Safanda M, Kotasek R, Jinkova S, Vanasek J, Seuwin B, Berdah JF, Boutruche B, Debourdeau P, Farge-Bancel D, Voog E, Agapé P, Bonnet I, Cornea CP, Ghiringhelli F, Henni S, Faehling M, von Pawel J, Langer F, Hoffmeister A, Ostermann H, Schmalenberg H, Fuxius S, Kirsch A, Bohnet S, Schem C, Karthaus M, Kretzschmar A, Zander T, Strumberg D, Klotz T, Hoehler T, Mohamed OF, Nogai A, Schulte C, Venerito M, Malfertheiner P, Beyer-Westendorf J, Kirchner H, Gaska T, Pelzer U, Meyer R, Prondzinsky R, Petty R, Lord H, McNamara M, Propper D, Khan O, Nokes T, Parkinson J, Farrugia D, Krell D, De Censi A, Passalacqua R, Pedrazzoli P, Verso M, Squizzato A, Petrelli F, Lodigiani C, Dvorkin M, Goldberg V, Orlov S, Alekseev S, Breder V, Kislov N, Nechaeva M, Orlova R, Lifirenko I, Tryakin A, Filippov A, Gladkov O, Poddubskaya E, Noguera C, Harish V, Roengvoraphoj Drescher M, Soff G, Tafur A, Billett H, Battini R, Jaslowski A, Wilbur D, Connolly G, Johnson S, Dhami M, Jurgens D, Loprinzi C, MacVicar G, Holladay C, Piatek C, Openshaw T, Arrambide K, Luckenbill J, Robinson M, Siddiqui B, Anderson T, Jain S, Saltzman M, Suh J, Tin-U C, Vaughn J, Calverley D, Halka K, Melear J, Schnadig I, Melnyk A, Pluard T, Encarnacion C, Lyons R, McKenney S, Seneviratne L, Streiff M, Sreenivasappa S, Buchanan G, DiSimone C, Andorsky D, DiBella N, Kleinman M, Kaklamani V, Rosovsky R, Sloan J, Stone S, Walls J, Islam R, Rajasekhar A, Wun T, Vasireddy VK, Costa D, Nguyen D, Greenwald D, Sousou T, Sohal D, Karamlou K, Seetharam M, Greenberg C, Patel J, Gaddh M, Garbo L, Slosky D, Lenihan D, Overman M, Lingerfelt B, Yimer H, Ramaekers R, Copur M, Lee C, Nakhl F, Kovoor P, O'Brien L, Aylesworth C, Patel K, Baltz B, Hadi G, Kaatz S, Kingsley E, McIntyre K, Prakash S, Diuguid D, Seastone D.

Author information

1
From the Department of Hematology and Medical Oncology, Taussig Cancer Institute and Case Comprehensive Cancer Center, Cleveland Clinic, Cleveland (A.A.K.); the Department of Medicine, Memorial Sloan Kettering Cancer Center (G.A.S., E.M.O.), and Weill Cornell Medical College (G.A.S., E.M.O.), New York; the Thrombosis Research Institute and University College London, London (A.K.K.); University of Texas M.D. Anderson Cancer Center, Houston (S.V.-R.), and U.S. Oncology Research-Texas Oncology, Tyler (H.A.Y.) - both in Texas; the Department of Medicine, Charité Universitätsmedizin Berlin, Berlin (H.R.); the Division of Hematology-Oncology, University of California Davis School of Medicine, Sacramento (T.W.), and the Keck School of Medicine, University of Southern California, Los Angeles (H.A.L.); the Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore (M.B.S.); the University of Washington School of Medicine (D.A.G., N.M.K., G.H.L.), Advanced Cancer Research Group (N.M.K.), and Fred Hutchinson Cancer Research Center (G.H.L.), Seattle; Penn State Cancer Institute, Milton S. Hershey Medical Center, Hershey, PA (C.P.B.); the Department of Cancer Pharmacology, Levine Cancer Institute, Atrium Health, Charlotte, NC (J.N.P.); Janssen Scientific Affairs, Titusville (P.W., P.B., S.K.), and Janssen Research and Development, Raritan (U.V.) - both in New Jersey; the Department of Medicine, McMaster University, Hamilton, ON, Canada (J.E.); the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (R.M.); and the Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston (K.A.B.).

Abstract

BACKGROUND:

Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.

METHODS:

In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding.

RESULTS:

Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).

CONCLUSIONS:

In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

PMID:
30786186
DOI:
10.1056/NEJMoa1814630
[Indexed for MEDLINE]

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