Semin Thromb Hemost 2013; 39(02): 117-126
DOI: 10.1055/s-0032-1333536
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Novel Oral Anticoagulants

Cristhiam M. Rojas-Hernandez
1   Division of Hematology/Oncology, University of New Mexico, Albuquerque, New Mexico
,
David A. Garcia
2   Division of Hematology, University of Washington, Seattle, Washington
› Author Affiliations
Further Information

Publication History

Publication Date:
06 February 2013 (online)

Abstract

After the introduction of warfarin, long-term oral anticoagulation treatment remained unchanged for more than 50 years. Most recently, with the development and approval of new oral anticoagulants, the treatment of medical conditions that require thrombosis prophylaxis and long-term anticoagulation has become more complex. In the case of venous thromboembolism (VTE) prevention after orthopedic surgery, the new oral agents will be less costly than the parenteral alternative. In other settings (such as atrial fibrillation or treatment of acute VTE), the new agents will offer additional convenience at higher cost, but the degree to which they will reduce clinically important events such as thrombosis or bleeding will be limited, especially for patients on optimally controlled warfarin. As the use of the new oral anticoagulants becomes more widespread, it will be important for all clinicians to have a basic understanding of their pharmacology, advantages, and limitations. Although the need to measure or reverse the effect of these drugs will arise infrequently, clinicians—especially hematologists—will desire evidence-based recommendations about how to manage such scenarios, which will require research studies.

 
  • References

  • 1 Pinto DJ, Orwat MJ, Koch S , et al. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem 2007; 50 (22) 5339-5356
  • 2 Wong PC, Jiang X. Apixaban, a direct factor Xa inhibitor, inhibits tissue-factor induced human platelet aggregation in vitro: comparison with direct inhibitors of factor VIIa, XIa and thrombin. Thromb Haemost 2010; 104 (2) 302-310
  • 3 Raghavan N, Frost CE, Yu Z , et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37 (1) 74-81
  • 4 Bristol-Myers Squibb/Pfizer. Eliquis® (INN - apixaban) Summary of Product Characteristics. http://ec.europa.eu/health/documents/community-register/2011/20110518102349/anx_102349_en.pdf
  • 5 Wang L, He K, Maxwell B , et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 2011; 39 (2) 256-264
  • 6 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 (4) 412-421
  • 7 Bayer Pharma AG. Xarelto® (INN - rivaroxaban) Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf . Accessed: February 1, 2013
  • 8 Lang D, Freudenberger C, Weinz C. In vitro metabolism of rivaroxaban, an oral, direct factor Xa inhibitor, in liver microsomes and hepatocytes of rats, dogs, and humans. Drug Metab Dispos 2009; 37 (5) 1046-1055
  • 9 Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 2011; 338 (1) 372-380
  • 10 Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64 (3) 292-303
  • 11 Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36 (2) 386-399
  • 12 Boehringer Ingelheim International GmbH. Pradaxa® (INN - dabigatran etexilate) Summary of Product Characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf . Accessed: February 1, 2013
  • 13 Härtter S, Koenen-Bergmann M, Sharma A , et al. Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. Br J Clin Pharmacol 2012; 74 (3) 490-500
  • 14 Boerhinger-Ingelheim. Dabigatran Advisory Committee Briefing Document. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm226009.pdf . Accessed: February 1, 2013
  • 15 Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361 (6) 594-604
  • 16 Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P. ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375 (9717) 807-815
  • 17 Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM. ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363 (26) 2487-2498
  • 18 Goldhaber SZ, Leizorovicz A, Kakkar AK , et al. ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365 (23) 2167-2177
  • 19 Buller H, Deitchman D, Prins M, Segers A. Botticelli Investigators, Writing Committee. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 6 (8) 1313-1318
  • 20 Alexander JH, Becker RC, Bhatt DL , et al. APPRAISE Steering Committee and Investigators. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009; 119 (22) 2877-2885
  • 21 Alexander JH, Lopes RD, James S , et al. APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365 (8) 699-708
  • 22 Granger CB, Alexander JH, McMurray JJ , et al. ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11) 981-992
  • 23 Eikelboom JW, O'Donnell M, Yusuf S , et al. Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 2010; 159 (3) 348 , e1
  • 24 Eriksson BI, Borris LC, Friedman RJ , et al. RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358 (26) 2765-2775
  • 25 Kakkar AK, Brenner B, Dahl OE , et al. RECORD2 Investigators. 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 (9632) 31-39
  • 26 Lassen MR, Ageno W, Borris LC , et al. RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358 (26) 2776-2786
  • 27 Turpie AG, Lassen MR, Davidson BL , et al. RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373 (9676) 1673-1680
  • 28 Turpie AG, Lassen MR, Eriksson BI , et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105 (3) 444-453
  • 29 Cohen AT, Spiro TE, Büller HR , et al. Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol. J Thromb Thrombolysis 2011; 31 (4) 407-416
  • 30 Cohen AT, Buller HR, Mebazaa A , et al. Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutely ill medical patients. The Annual Scientific Session of the American College of Cardiology. New Orleans, LA, 2011
  • 31 Bauersachs R, Berkowitz SD, Brenner B , et al. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
  • 32 Büller HR, Prins MH, Lensin AW , et al. EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
  • 33 Mega JL, Braunwald E, Wiviott SD , et al. ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366 (1) 9-19
  • 34 Patel MR, Mahaffey KW, Garg J , et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
  • 35 Eriksson BI, Dahl OE, Rosencher N , et al. RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370 (9591) 949-956
  • 36 Eriksson BI, Dahl OE, Rosencher N , et al. RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5 (11) 2178-2185
  • 37 Ginsberg JS, Davidson BL, Comp PC , et al. RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24 (1) 1-9
  • 38 Schulman S, Kearon C, Kakkar AK , et al. RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
  • 39 Schulman S, Baanstra D, Eriksson H , et al. Dabigatran versus Placebo for Extended Maintenance Therapy of Venous Thromboembolism. ISTH, Kyoto, Japan; 2011
  • 40 Schulman S, Kakkar AK, Schellong SM , et al. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II). The American Society of Hematology 2011 Annual Meeting. San Diego, CA, 2011
  • 41 Schulman S, Eriksson H, Goldhaber SZ , et al. Dabigatran or Warfarin for Extended Maintenance Therapy of Venous Thromboembolism. ISTH, Kyoto, Japan; 2011
  • 42 Oldgren J, Budaj A, Granger CB , et al. RE-DEEM Investigators. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011; 32 (22) 2781-2789
  • 43 Connolly SJ, Ezekowitz MD, Yusuf S , et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
  • 44 Eikelboom JW, Wallentin L, Connolly SJ , et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123 (21) 2363-2372
  • 45 Beasley BN, Unger EF, Temple R. Anticoagulant options—why the FDA approved a higher but not a lower dose of dabigatran. N Engl J Med 2011; 364 (19) 1788-1790
  • 46 Adam SS, McDuffie JR, Ortel TL, Williams Jr JW. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med 2012;
  • 47 Samama MM, Martinoli JL, LeFlem L , et al. Assessment of laboratory assays to measure rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103 (4) 815-825
  • 48 Lindahl TL, Baghaei F, Blixter IF , et al. Expert group on coagulation of the external quality assurance in laboratory medicine in Sweden. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 2011; 105 (2) 371-378
  • 49 Avecilla ST, Ferrell C, Chandler WL, Reyes M. Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol 2012; 137 (4) 572-574
  • 50 Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23 (2) 138-143
  • 51 Kaatz S, Kouides PA, Garcia DA , et al. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Am J Hematol 2012; 87 (Suppl. 01) S141-S145
  • 52 Ganetsky M, Babu KM, Salhanick SD, Brown RS, Boyer EW. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol 2011; 7 (4) 281-287
  • 53 Al-Horani RA, Ponnusamy P, Mehta AY, Gailani D, Desai UR. Sulfated Pentagalloylglucoside Is a Potent, Allosteric, and Selective Inhibitor of Factor XIa. J Med Chem 2013; (e-pub ahead of print)
  • 54 Ahrens I, Peter K, Lip GY, Bode C. Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Discov Med 2012; 13 (73) 445-450