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Supplemental Digital Content
Main papers and guidelines analyzed
Rivaroxaban Pharmacokinetics/Pharmacodynamics
Mueck W, Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman M V., et al. Rivaroxaban for Thromboprophylaxis in Patients Undergoing Total Hip Replacement: Comparison of Pharmacokinetics and Pharmacodynamics with Once- and Twice-Daily Dosing. ASH Annu Meet Abstr 2006;108:903.
Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–21.
Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, et al. Effects of renal
impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010;70:703–12
Perzborn E, Strassburger J, Wilmen A, Pohlmann J, Roehrig S, Schlemmer K-H, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–21
Depasse F, Busson J, Mnich J, et al. Effect of BAY 59-7939 - a novel, oral, direct Factor Xa inhibitor - on clot-bound Factor Xa activity in vitro. J Thromb Haemost 2005; 3 (Suppl 1):
Abstract P1104.
Papers
Turpie AGG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost 2012;108:876–86.
Wasserlauf G, Grandi SM, Filion KB, Eisenberg MJ. Meta-Analysis of Rivaroxaban and Bleeding Risk. Am J Cardiol 2013;112:454–60.
Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants:
pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J 2013;11:10.
Büller HR, Prins MH, Lensin AWA, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97.
Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral
rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499–510.
Mega JL, Braunwald E, Wiviott SD, Bassand J-P, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19.
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Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
Palareti G, Ageno W, Ferrari A, Filippi A, Imberti D, Pengo V, et al. Clinical management of rivaroxaban-treated patients. Expert Opin Pharmacother 2013;14:655–67.
Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Crackowski JL, et al. Effect of non- specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a
randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012;108:217–
24.
Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo- controlled, crossover study in healthy subjects. Circulation 2011;124:1573–9.
Zhou W, Zorn M, Nawroth P, Bütehorn U, Perzborn E, Heitmeier S, et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with rivaroxaban. Stroke 2013;44:771–
8.
Helin TA, Pakkanen A, Lassila R, Joutsi-Korhonen L. Laboratory Assessment of Novel Oral Anticoagulants: Method Suitability and Variability between Coagulation Laboratories. Clin Chem 2013;59:807–14.
Gruber A, Marzec UM, Buetehorn U et al. Potential of activated prothrombin complex concentrate and activated Factor VII to reverse the anticoagulant effects of rivaroxaban in primates. Blood (ASH Annual Meeting Abstracts) 2008: 112, 1307. Abstract 3825.
Perzborn E, Tinel H. FEIBA reverses the effects of a high dose of rivaroxaban in rats.
Pathophysiol Haemost Thromb 2008: 36: A40. Abstract P061.
Lu G, DeGuzman FR, Lakhotia . et al. Recombinant antidote for reversal of anticoagulation by Factor Xa inhibitors. Blood (ASH Annual Meeting Abstracts) 2008: 112. Abstract 983.
Lu G, Luan P, Hollenbach S et al. Reconstructed recombinant Factor Xa as an antidote to reverse anticoagulation by Factor Xa inhibitors. J Thromb Haemost 2009: 7, Suppl. 2.
Abstract OC-TH-107
Hutchaleelaha A, Lu G, Deguzman FR, et al. Recombinant factor Xa inhibitor antidote (PRT064445) mediates reversal of anticoagulation through reduction of free drug
concentration: a common mechanism for direct factor Xa inhibitors. European Heart Journal 2012: 33 (Abstract Supplement), 496.ß
Guidelines
Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation:
executive summary. Eur Heart J 2013;34:2094–106.
Lip GYH, Windecker S, Huber K, Kirchhof P, Marin F, Ten Berg JM, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint
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consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous
Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS.
Eur Heart J 2014;35:3155–79
Camm AJ, Lip GYH, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special
contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719–47.
NICE technology appraisal guidance 261: 2012. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism.
http://www.nice.org.uk/guidance/ta261.
Clinical trials on rivaroxaban
o.d., once daily; t.d., twice daily; VTE, venous thromboembolis; THR, total hip replacement; TKR, total knee replacement; VKA, vitamin K antagonist; PE, pulmonary embolism; DVT, deep vein thrombosis; NVAF, non valvular atrial fibrillation; CV, cardiovascular;
ACS, acute coronary syndrome * At 10 days
Trial Design Drug Comparator Indication Patients
(n)
Primary outcome Major bleeding Drug (%) vs Comparator (%), p-value Record 1
[1]
Randomized double-blind, non-inferiority
Rivaroxaban 10 mg o.d.; 5 weeks
Enoxaparin 40 mg o.d.;
5 weeks
Prevention of VTE after THR
4541 1.1 vs 3.7, p<0.001 (superiority)
0.3 vs 0.1, p=0.18
Record 2 [2]
Randomized double-blind, non-inferiority
Rivaroxaban 10 mg o.d.; 5 weeks
Enoxaparin 40 mg o.d.;
10-14 days
Prevention of VTE after THR
2509 2 vs 9.3, p<0.0001 (superiority)
<0.1 vs <0.1, p=0.25
Record 3 [3]
Randomized double-blind, non-inferiority
Rivaroxaban 10 mg o.d.;
10-14 days
Enoxaparin 40 mg o.d.;
10-14 days
Prevention of VTE after TKR
2531 9.6 vs 18.9, p<0.001 (superiority)
0.6 vs 0.5, p=0.77
Record 4 [4]
Randomized double-blind, non-inferiority
Rivaroxaban 10 mg o.d.;
10-14 days
Enoxaparin 30 mg t.d.;
10-14 days
Prevention of VTE after TKR
3148 6.9 vs 10.1, p=0.0118 (superiority)
0.7 vs 0.3, p=0.1096
Magellan [5]
Randomized double-blind, non-inferiority
Rivaroxaban 10 mg o.d.;
31-39 days
Enoxaparin 30 mg t.d.;
6-14 days
Prevention of VTE in medical ill patients
8101 4.4 vs 5.7, p=0.0025 (non- inferiority)
0.6 vs 0.3, p=0.03*
Einstein DVT [6]
Randomized open label
Rivaroxaban 15 mg t.d.; 3 weeks;
followed by 20 mg o.d.
VKA Treatment of
acute DVT
3449 2.1 vs 3.0, p<0.001 (non- inferiority)
00.8 vs 1.2, p=0.21
Einstein PE [7]
Randomized open label
Rivaroxaban 15 mg t.d.; 3 weeks;
followed by 20 mg o.d.
Enoxaparin followed by VKA
Treatment of acute PE
4832 2.1 vs 1.8, p=0.003 (non- inferiority)
1.1 vs 2.2, p=0.003
Einstein EXT [6]
Randomized double-blind
Rivaroxaban 20 mg o.d.; 6 or 12 months
Placebo Treatment of VTE
1196 1.3 vs 7.1, p<0.001 (superiority)
0.7 vs 0, p=0.11
ROCKET AF [8]
Randomized double-blind
Rivaroxaban 20 mg o.d.
Warfarin Prevention of stroke in NVAF patients
14266 2.12 vs 2.42 p<0.001 (non- inferiority)
5.6 vs 5.4, p=0.58
Atlas ACS 2 TIMI 51 [9]
Randomized double-blind
Rivaroxaban 2.5 or 5 mg t.d.; 13-31 months
Placebo Prevention of CV events in ACS patients
15526 8.9 vs 10.7, p=0.008
2.1 vs 0.6, p=0.009
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References
1 Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman M V, Kakkar AK, et al.
Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765–75.
2 Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008;372:31–9.
3 Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, et al.
Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.
N Engl J Med 2008;358:2776–86.
4 Turpie AGG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, et al.
Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009;373:1673–80.
5 Cohen AT, Spiro TE, Büller HR, Haskell L, Hu D, Hull R, et al. Rivaroxaban for
thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513–23.
6 Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med
2010;363:2499–510.
7 Büller HR, Prins MH, Lensin AWA, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287–97.
8 Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91.
9 Mega JL, Braunwald E, Wiviott SD, Bassand J-P, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9–19.
