Current Cardiology Reports

, Volume 6, Issue 5, pp 354–364 | Cite as

New approaches to anticoagulation in atrial fibrillation

  • Palle Petersen
Article

Abstract

Oral direct thrombin inhibitors (DTIs) are a potential alternative to vitamin K antagonists, such as warfarin, for anticoagulant therapy. The oral DTI at the most advanced stage of clinical development is ximelagatran, which is rapidly absorbed and bioconverted to the active form melagatran. Oral ximelagatran has been evaluated in randomized, controlled trials for several indications, including stroke prevention in atrial fibrillation (AF). Recently, two pivotal phase III trials demonstrated that fixed-dose oral ximelagatran, 36 mg twice daily without coagulation monitoring, prevents stroke and systemic embolic events in patients with nonvalvular AF as effectively as well-controlled, adjusted-dose warfarin. Oral ximelagatran was generally well tolerated and caused less total (major plus minor) bleeding than warfarin. In a minority of ximelagatran-treated patients, elevated serum alanine aminotransferase levels were reported, but were typically not associated with specific symptoms, and returned toward the pretreatment baseline whether treatment was continued or discontinued. In AF, oral ximelagatran promises a better benefit to risk ratio than warfarin.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Murray CJL, Lopez AD, Mathers CD, Stein C: The global burden of disease 2000 project: aims, methods and data sources. Global Programme on Evidence for Health Policy — Discussion Papers, No. 36. Geneva: World Health Organization; 2001.Google Scholar
  2. 2.
    Public health and aging: hospitalizations for stroke among adults aged ⩾=65 years-United States, 2000. MMWR 2003, 52:586–589.Google Scholar
  3. 3.
    Wolf PA, Abbott RD, Kannel WB: Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991, 22:983–988.PubMedGoogle Scholar
  4. 4.
    Falk RH: Atrial fibrillation. N Engl J Med 2001, 344:1067–1078.PubMedCrossRefGoogle Scholar
  5. 5.
    Singer DE: A 60-year-old woman with atrial fibrillation. JAMA 2003, 290:2182–2189.PubMedCrossRefGoogle Scholar
  6. 6.
    EAFT (European Atrial Fibrillation Trial) Study Group: Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993, 342:1255–1262.Google Scholar
  7. 7.
    Conway DS, Heeringa J, Van Der Kuip DA, et al.: Atrial fibrillation and the prothrombotic state in the elderly: the Rotterdam Study. Stroke 2003, 34:413–417.PubMedCrossRefGoogle Scholar
  8. 8.
    Kahn SR, Solymoss S, Flegel KM: Nonvalvular atrial fibrillation: evidence for a prothrombotic state. CMAJ 1997, 157:673–681.PubMedGoogle Scholar
  9. 9.
    Kamath S, Blann AD, Caine GJ, et al.: Platelet P-selectin levels in relation to plasma soluble P-selectin and beta-thromboglobulin levels in atrial fibrillation. Stroke 2002, 33:1237–1242.PubMedCrossRefGoogle Scholar
  10. 10.
    Kamath S, Chin BS, Blann AD, Lip GY: A study of platelet activation in paroxysmal, persistent and permanent atrial fibrillation. Blood Coagul Fibrinolysis 2002, 13:627–636.PubMedCrossRefGoogle Scholar
  11. 11.
    Kamath S, Blann AD, Chin BS, Lip GY: Platelet activation, haemorheology and thrombogenesis in acute atrial fibrillation: a comparison with permanent atrial fibrillation. Heart 2003, 89:1093–1095.PubMedCrossRefGoogle Scholar
  12. 12.
    Conway DS, Pearce LA, Chin BS, et al.: Plasma von Willebrand factor and soluble p-selectin as indices of endothelial damage and platelet activation in 1321 patients with nonvalvular atrial fibrillation: relationship to stroke risk factors. Circulation 2002, 106:1962–1967.PubMedCrossRefGoogle Scholar
  13. 13.
    Conway DS, Pearce LA, Chin BS, et al.: Prognostic value of plasma von Willebrand factor and soluble P-selectin as indices of endothelial damage and platelet activation in 994 patients with nonvalvular atrial fibrillation. Circulation 2003, 107:3141–3145.PubMedCrossRefGoogle Scholar
  14. 14.
    Feinberg WM, Blackshear JL, Laupacis A, et al.: Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995, 155:469–473.PubMedCrossRefGoogle Scholar
  15. 15.
    Albers GW, Dalen JE, Laupacis A, et al.: Antithrombotic therapy in atrial fibrillation. Chest 2001, 119:194S-206S.PubMedCrossRefGoogle Scholar
  16. 16.
    United Nations: World Population Prospects. The 2002 Revision. Highlights. No. Draft, ESA/P/WP.165. New York: United Nations; 2001.Google Scholar
  17. 17.
    Go AS, Hylek EM, Phillips KA, et al.: Prevalence of diagnosed atrial fibrillation in adults — National implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA 2001, 285:2370–2375.PubMedCrossRefGoogle Scholar
  18. 18.
    Atrial Fibrillation Investigators: Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994, 154:1449–1457.CrossRefGoogle Scholar
  19. 19.
    Hart RG, Benavente O, McBride R, Pearce LA: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999, 131:492–501.PubMedGoogle Scholar
  20. 20.
    Fuster V, Rydén LE, Asinger RW, et al.: ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. J Am Coll Cardiol 2001, 38:1231–1265.PubMedCrossRefGoogle Scholar
  21. 21.
    Bungard TJ, Ghali WA, Teo KK, et al.: Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 2000, 160:41–46.PubMedCrossRefGoogle Scholar
  22. 22.
    Gottlieb LK, Salem-Schatz S: Anticoagulation in atrial fibrillation. Does efficacy in clinical trials translate into effectiveness in practice? Arch Intern Med 1994, 154:1945–1953.PubMedCrossRefGoogle Scholar
  23. 23.
    Gurwitz JH, Monette J, Rochon PA, et al.: Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Arch Intern Med 1997, 157:978–984.PubMedCrossRefGoogle Scholar
  24. 24.
    Malik AK, Taylor AJ: Can warfarin randomized trials be reproduced in ‘real life’? Adherence to warfarin guidelines for intensity of anticoagulation in a university-based warfarin clinic. South Med J 2000, 93:58–61.PubMedGoogle Scholar
  25. 25.
    Elg M, Gustafsson D, Carlsson S: Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat. Thromb Res 1999, 94:187–197.PubMedCrossRefGoogle Scholar
  26. 26.
    Hirsh J, Dalen J, Anderson DR, et al.: Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001, 119:8S-21S.PubMedCrossRefGoogle Scholar
  27. 27.
    Ansell J, Hirsh J, Dalen J, et al.: Managing oral anticoagulant therapy. Chest 2001, 119:22S-38S.PubMedCrossRefGoogle Scholar
  28. 28.
    Hylek EM, Go AS, Chang Y, et al.: Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003, 349:1019–1026.PubMedCrossRefGoogle Scholar
  29. 29.
    Levine MN, Raskob G, Landefeld S, Kearon C: Hemorrhagic complications of anticoagulant treatment. Chest 2001, 119:108S-121S.PubMedCrossRefGoogle Scholar
  30. 30.
    Hylek EM, Singer DE: Risk-factors far intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994, 120:897–902.PubMedGoogle Scholar
  31. 31.
    Elg M, Gustafsson D, Deinum J: The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. Thromb Haemost 1997, 78:1286–1292.PubMedGoogle Scholar
  32. 32.
    Hirsh J, Fuster V, Ansell J, Halperin JL: American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003, 107:1692–1711.PubMedCrossRefGoogle Scholar
  33. 33.
    Tabrizi AR, Zehnbauer BA, Borecki IB, et al.: The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg 2002, 194:267–273.PubMedCrossRefGoogle Scholar
  34. 34.
    Dahlback B: Blood coagulation. Lancet 2000, 355:1627–1632.PubMedCrossRefGoogle Scholar
  35. 35.
    Harker LA, Hanson SR, Runge MS: Thrombin hypothesis of thrombus generation and vascular lesion formation. Am J Cardiol 1995, 75:12B-17B.PubMedCrossRefGoogle Scholar
  36. 36.
    Polack B: [Thrombin: a multifunctional enzyme]. Ann Biol Clin (Paris) 2003, 61:23–31.Google Scholar
  37. 37.
    Petersen P, Grind M, Adler J, SPORTIF II Investigators: Ximelagatran versus warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. SPORTIF II: a dose-guiding, tolerability, and safety study. J Am Coll Cardiol 2003, 41:1445–1451. This randomized, phase II trial demonstrated the tolerability and general safety of thromboprophylaxis with oral ximelagatran, administered in fixed doses of up to 60 mg twice daily over 12 weeks, without coagulation monitoring, in 187 moderate- to high-risk patients with nonvalvular AF. The risks of TIA, stroke, or bleeding among these patients were similar to those among 67 patients treated with dose-adjusted warfarin (INR, 2.0-3.0). Elevations of serum S-ALAT among eight patients (4.3%) in the ximelagatran group were transient and were not associated with specific symptoms.PubMedCrossRefGoogle Scholar
  38. 38.
    Halperin JL, and the Executive Steering Committee on behalf of the SPORTIF III and V Study Investigators: Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V). Am Heart J 2003, 146:431–438. SPORTIF III and V were the pivotal, randomized, phase III efficacy trials of ximelagatran in patients with nonvalvular AF. Both trials tested the hypothesis that fixed-dose oral ximelagatran (36 mg twice daily, without coagulation monitoring) prevents stroke and SEEs at least as effectively as dose-adjusted warfarin (target INR, 2.0-3.0). The only difference in trial design was that in SPORTIF III (Europe/Asia/Australasia; 259 centers), treatment administration was open label, whereas in SPORTIF V (North America; 409 centers) treatment was double-blind.PubMedCrossRefGoogle Scholar
  39. 39.
    Executive Steering Committee on behalf of the SPORTIF V investigators: Efficacy and safety study of the oral direct thrombin inhibitor ximelagatran compared with doseadjusted warfarin in the prevention of stroke and systemic embolic events in patients with atrial fibrillation (SPORTIF V). Circulation 2003, 108:21. SPORTIF V (n = 3922) has confirmed the noninferiority of fixed-dose oral ximelagatran, relative to warfarin, for prevention of stroke and SEEs in patients with nonvalvular AF. Bleeding risk was similar in the ximelagatran and warfarin groups, whereas transient elevations of serum S-ALAT occurred in 6.0% and 0.8% of patients, respectively.CrossRefGoogle Scholar
  40. 40.
    Executive Steering Committee on behalf of the SPORTIF III Investigators: Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003, 362:1691–1698. In SPORTIF III trial (n = 3407), one of two pivotal phase III efficacy trials, oral ximelagatran, 36 mg twice daily without coagulation monitoring, prevented strokes and SEEs at least as effectively as carefully doseadjusted warfarin (INR, 2.0-3.0), and caused less bleeding than warfarin. Ximelagatran was generally well tolerated and, although it was more frequently associated with elevations of serum S-ALAT, these were not associated with specific symptoms in any patient, and returned toward normal whether or not treatment was continued.CrossRefGoogle Scholar
  41. 41.
    Colwell CW, Berkowitz SD, Davidson BL, et al.: Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, doubleblind study. J Thromb Haemost 2003, 1:2119–2130.PubMedCrossRefGoogle Scholar
  42. 42.
    Colwell CW, Berkowitz SD, Comp PC, et al.: Randomized, double-blind comparison of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee replacement (TKR): EXULT B. Blood 2003, 102:11.Google Scholar
  43. 43.
    Eriksson BI, Agnelli G, Cohen AT, et al.: Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO III study. Thromb Haemost 2003, 89:288–296.PubMedGoogle Scholar
  44. 44.
    Eriksson BI, Dahl OE: Prevention of venous thromboembolism following orthopaedic surgery: clinical potential of direct thrombin inhibitors. Drugs 2004, 64:577–595.PubMedCrossRefGoogle Scholar
  45. 45.
    Eriksson BI, Agnelli G, Cohen AT, et al.: The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. J Thromb Haemost 2003, 1:2490–2496.PubMedCrossRefGoogle Scholar
  46. 46.
    Eriksson BI, Bergqvist D, Kälebo P, et al.: Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002, 360:1441–1447.PubMedCrossRefGoogle Scholar
  47. 47.
    Evans HC, Perry CM, Faulds D: Ximelagatran/melagatran: a review of its use in the prevention of venous thromboembolism in orthopaedic surgery. Drugs 2004, 64:649–678.PubMedCrossRefGoogle Scholar
  48. 48.
    Francis CW, Davidson BL, Berkowitz SD, et al.: Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, doubleblind trial. Ann Intern Med 2002, 137:648–655.PubMedGoogle Scholar
  49. 49.
    Francis CW, Berkowitz SD, Comp PC, et al.: Comparison of Ximelagatran with Warfarin for the Prevention of Venous Thromboembolism after Total Knee Replacement. N Engl J Med 2003, 349:1703–1712.PubMedCrossRefGoogle Scholar
  50. 50.
    Heit JA, Colwell CW, Francis CW, et al.: Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: a phase 2 dose-finding study. Arch Intern Med 2001, 161:2215–2221.PubMedCrossRefGoogle Scholar
  51. 51.
    Exanta™ (Ximelagatran) receives first approval. Thrombos Haemost 2004, 91:VIII.Google Scholar
  52. 52.
    Wåhlander K, Lapidus L, Olsson C-G, et al.: Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res 2002, 107:93–99.PubMedCrossRefGoogle Scholar
  53. 53.
    Eriksson H, Wåhlander K, Gustafsson D, et al.: A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. J Thromb Haemost 2003, 1:41–47.PubMedCrossRefGoogle Scholar
  54. 54.
    Schulman S, Wåhlander K, Lundström T, et al.: Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003, 349:1713–1721.PubMedCrossRefGoogle Scholar
  55. 55.
    Gustafsson D, Nyström J-E, Carlsson S, et al.: The direct thrombin inhibitor melagatran and its oral prodrug H 376/95: intestinal absorption properties, biochemical and pharmacodynamic effects. Thromb Res 2001, 101:171–181.PubMedCrossRefGoogle Scholar
  56. 56.
    Eriksson UG, Bredberg U, Gislén K, et al.: Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003, 59:35–43.PubMedGoogle Scholar
  57. 57.
    Eriksson UG, Bredberg U, Hoffmann K-J, et al.: Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2003, 31:294–305.PubMedCrossRefGoogle Scholar
  58. 58.
    Johansson LC, Frison L, Logren U, et al.: Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003, 42:381–392.PubMedCrossRefGoogle Scholar
  59. 59.
    Johansson LC, Andersson M, Fager G, et al.: No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers. Clin Pharmacokinet 2003, 42:475–484.PubMedCrossRefGoogle Scholar
  60. 60.
    Sarich TC, Teng R, Peters GR, et al.: No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003, 42:485–492.PubMedCrossRefGoogle Scholar
  61. 61.
    Bredberg E, Andersson TB, Frison L, et al.: Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003, 42:765–777.PubMedCrossRefGoogle Scholar
  62. 62.
    Wåhlander K, Eriksson-Lepkowska M, Frison L, et al.: No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003, 42:755–764.PubMedCrossRefGoogle Scholar
  63. 63.
    Sarich TC, Johansson S, Schützer K-M, et al.: The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, are unaffected by a single dose of alcohol. J Clin Pharmacol 2004, 44:388–393.PubMedCrossRefGoogle Scholar
  64. 64.
    Wolzt M, Boström SL, Svensson M, et al.: Effects of the oral direct thrombin inhibitor ximelagatran on P-selectin expression and thrombin generation in atrial fibrillation. Pathophysiol Haemost Thromb 2003, 33:68–74. This open-label phase I study investigated the pharmacodynamic (antiplatelet and anticoagulant) effects of intravenous melagatran, 2.66 mg stat (day 1) and oral ximelagatran, 36 mg twice daily (days 2–6). P-selectin expression in 12 patients with nonvalvular AF was 45% higher than in 12 group-matched healthy volunteers on day 1 (pretreatment), but decreased to the levels seen in volunteers by day 6. Thrombin generation was delayed and inhibited in both groups.PubMedCrossRefGoogle Scholar
  65. 65.
    Wolzt M, Wollbratt M, Svensson M, et al.: Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and healthy subjects. Eur J Clin Pharmacol 2003, 59:537–543. The PK profiles of iv melagatran and oral ximelagatran in 12 elderly patients with nonvalvular AF were shown to be consistent with those observed in 12 group-matched, healthy controls.PubMedCrossRefGoogle Scholar
  66. 66.
    Eriksson U, Bååthe S, Hamrén B, et al.: Predictable pharmacokinetics of ximelagatran, an oral direct thrombin inhibitor, in nonvalvular atrial fibrillation patients receiving long-term treatment. Pathophysiol Haemost Thromb 2002, 32(Suppl 2):56.Google Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Palle Petersen
    • 1
  1. 1.Department of NeurologyCopenhagen University HospitalCopenhagen ØDenmark

Personalised recommendations