A Step Change in Oral Anticoagulation: Lack of Coagulation Monitoring with Ximelagatran

ABSTRACT

The clinical development of ximelagatran for the treatment and prevention of various arterial and venous thromboembolic disorders has used fixed-dose regimens without coagulation monitoring in all indications. Although monitoring is not required, effects on the various coagulation assays that are available are seen with its active form melagatran, and there are situations where an assessment of anticoagulant effect may help to inform clinical decisions. However, the sensitivity of different coagulation assays varies considerably. The thrombin clotting time (TT) and ecarin clotting time (ECT) are highly sensitive to plasma melagatran concentrations (IC₅₀ ∼0.01 μmol/L and ∼0.15 μmol/L, respectively), with an approximate linear relationship between plasma melagatran concentration and prolongation of clotting time. In comparison, the activated partial thromboplastin time (APTT) (IC₅₀ ∼0.3 to 0.8 μmol/L) and prothrombin time (PT) (IC₅₀ ∼0.9 to 2.9 μmol/L) are relatively insensitive, and the concentration-response relationship shows a flattening with increasing plasma melagatran concentration. Commercially available APTT and PT reagents varied considerably in their sensitivity to melagatran. Comparing the various coagulation assays, the APTT, ECT, and TT are suitable choices when an indicator of the anticoagulant effect of ximelagatran is required, although the absence of international standards requires calibration of each test in individual laboratories and the ECT is not widely available.

KEYWORDS

Ximelagatran - coagulation monitoring - prothrombin time - activated partial thromboplastin time

REFERENCES

• 1 Anderson R J. Cost analysis of a managed care decentralized outpatient pharmacy anticoagulation service.  J Manag Care Pharm. 2004;  10 159-165
• 2 McCormick D, Gurwitz J H, Goldberg R J et al.. Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting.  Arch Intern Med. 2001;  161 2458-2463
• 3 Lackner T E, Battis G N. Use of warfarin for nonvalvular atrial fibrillation in nursing home patients.  Arch Fam Med. 1995;  4 1017-1026
• 4 Francis C W, Berkowitz S D, Comp P C 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
• 5 Eriksson B I, 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
• 6 Eriksson B I, Agnelli G, Cohen A T 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.  Thromb Haemost. 2003;  89 288-296
• 7 Eriksson B I, Agnelli G, Cohen A T 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
• 8 Petersen P, Grind M, Adler J. 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
• 9 Olsson S B. 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
• 10 Schulman S, Wåhlander K, Lundström T, Clason S B, Eriksson H. THRIVE III Investigators . Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.  N Engl J Med. 2003;  349 1713-1721
• 11 Wallentin L, Wilcox R G, Weaver W D et al.. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial.  Lancet. 2003;  362 789-797
• 12 Carlsson S C, Mattson C, Eriksson U G et al.. A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays.  Thromb Res. 2005;  115(1-2) 9-18
• 13 Eriksson U G, 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
• 14 Wolzt M, Boström S L, Svensson M, Wåhlander K, Grind M, Sarich T C. 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
• 15 Wolzt M, Wollbratt M, Svensson M, Wåhlander K, Grind M, Eriksson U G. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.  Eur J Clin Pharmacol. 2003;  59 537-543
• 16 Sarich T C, Eriksson U G, Mattsson C et al.. Inhibition of thrombin generation by the oral direct thrombin inhibitor ximelagatran in shed blood from healthy male subjects.  Thromb Haemost. 2002;  87 300-305
• 17 Sarich T C, Wolzt M, Eriksson U G et al.. Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects.  J Am Coll Cardiol. 2003;  41 557-564
• 18 Eriksson U G, 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
• 19 Bergqvist D, Solhaug J H, Holmdahl L, Eriksson U G, Andersson M, Ögren M. Pharmacokinetics, preliminary efficacy and safety of subcutaneous melagatran and oral ximelagatran: a multicentre study of thromboprophylaxis in elective abdominal surgery.  Clin Drug Investig. 2004;  24 127-136
• 20 Johansson S, Wåhlander K, Larson G, Ohlsson L, Larsson M, Eriksson U G. Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men.  Blood Coagul Fibrinolysis. 2003;  14 677-684
• 21 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
• 22 Eriksson U G, Mandema J W, Karlsson M O et al.. Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran: a population model analysis.  Clin Pharmacokinet. 2003;  42 687-701
• 23 Johansson L C, Frison L, Logren U, Fager G, Gustafsson D, Eriksson U G. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;  42 381-392
• 24 Sarich T C, Teng R, Peters G R 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
• 25 Johansson L C, Andersson M, Fager G, Gustafsson D, Eriksson U G. 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
• 26 Eriksson U G, Johansson S, Attman P O et al.. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran.  Clin Pharmacokinet. 2003;  42 743-753
• 27 Wåhlander K, Eriksson-Lepkowska M, Frison L, Fager G, Eriksson U G. 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
• 28 Sarich T C, Johansson S, Schützer K J et al.. The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct inhibitor, are unaffected by a single dose of alcohol.  J Clin Pharmacol. 2004;  44 388-393
• 29 Fager G, Cullberg M, Eriksson-Lepkowska M, Frison L, Eriksson U G. Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid.  Eur J Clin Pharmacol. 2003;  59 283-289
• 30 Sarich T C, Schützer K M, Dorani H et al.. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran.  J Clin Pharmacol. 2004;  44 928-934
• 31 Sarich T C, Schützer K M, Wollbratt M, Wall U, Kessler E, Eriksson U G. No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers.  J Clin Pharmacol. 2004;  44 935-941
• 32 Teng R, Sarich T C, Eriksson U G et al.. A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor.  J Clin Pharmacol. 2004;  44 1063-1071
• 33 Bredberg E, Andersson T B, 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
• 34 Mattsson C, Menschiek-Lundin A, Wahlander K, Lindahl T L. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample.  Thromb Haemost. 2001;  86 611-615
• 35 Gustafsson D, Antonsson T, Bylund R et al.. Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes.  Thromb Haemost. 1998;  79 110-118
• 36 Potzsch B, Hund S, Madlener K, Unkrig C, Muller-Berghaus G. Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay.  Thromb Res. 1997;  86 373-383
• 37 Fenyvesi T, Jörg I, Harenberg J. Effect of phenprocoumon on monitoring of lepirudin, argatroban, melagatran and unfractionated heparin with the PiCT method.  Pathophysiol Haemost Thromb. 2002;  32 174-179