The influence on INRs and coagulation factors of the time span between blood sample collection and intake of phenprocoumon or acenocoumarol: Consequences for the assessment of the dose

Summary

Managing treatment with vitamin K antagonists, the prothrombin time (PT),expressed as international normalized ratio (INR), may not represent the INR during the entire 24 hour (h) period, and this variation may be different between long-acting phenprocoumon and short-acting acenocoumarol. For both drugs we investigated the variation in 24 h of the PT/INR, the consequences for the assessment of the doses and which vitamin K-dependent factor causes the daily variation. Patients on self-management took their medication at 6 p.m. and determined their INRs for eight weeks, once a week and three times daily (8.30 a.m., 6 p.m. and 11 p.m., thus 14.5 h, 24 h and 29 h after taking the medication, respectively). Acenocoumarol showed a significant variation in INRs over the 24 h period, with 22 out of 80 INRs >20% lower at 11 p.m. versus 8.30 a.m. Phenprocoumon showed only few variations. Patients managed by the anticoagulation clinic took their medication at 6 p.m. for four weeks and then at 8 a.m. for four weeks, 15 h and 25 h, respectively, before the weekly blood collection. PT/INR and coagulation factorsVII, X and II were determined. With acenocoumarol, taken 25 h before blood collection, the INRs were significantly different compared to 15 h, especially attributed to plasma levels of factorVII. Those on phenprocoumon were equal. These variations of INRs during 24 h may have major effects on the prescribed dose of short-acting vitamin K antagonists, such as acenocoumarol, especially for INRs at the limits of the therapeutic ranges.

Keywords

Acenocoumarol - phenprocoumon - INR variation in 24 h - coagulation factor variation in 24 h

• References

• 1 Ansell J, Hirsh J, Poller L. et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.. Chest 2004; 204S-233S.
• 2 Poller L. International Normalized Ratios (INR): 20 years.. J Thromb Haemost 2004; 2: 849-860.
• 3 Van Geest-Daalderop JHH, Mulder AB, Boonmande Winter LJM. et al. Preanalytical variables and offsite blood collection: influences on the results of the prothrombin time/international normalized ratio test and implications for monitoring of oral anticoagulant therapy.. Clin Chem 2005; 51: 561-568.
• 4 Laporte S, Quenet S, Buchmüller-Cordier A. et al. Compliance and stability of INR of two oral anticoagulants with different half-lives: a randomised trial.. Thromb Haemost 2003; 89: 458-467.
• 5 Rosendaal FR, Cannegieter SC, van der Meer FJM. et al. A method to determine the optimal intensity of oral anticoagulation therapy.. Thromb Haemost 1993; 69: 236-239.
• 6 Haustein KO. Pharmacokinetic and pharmacodynamic properties of oral anticoagulants, especially phenprocoumon.. Sem Thromb Hemost 1999; 25: 5-11.
• 7 Van Geest-Daalderop JHH, Sturk A, Levi M. et al. Extent and quality of anticoagulation treatment with coumarin derivatives by the Dutch Thrombosis Services.. Ned Tijdschr Geneesk 2004; 148: 730-735.
• 8 Gadisseur APA, van der Meer FJM, Adriaansen HJ. et al. Therapeutic quality control of oral anticoagulant therapy comparing the short-acting acenocoumarol and the long-acting phenprocoumon.. Br J Haematol 2002; 117: 940-946.
• 9 Fihn SD, Gadisseur APA, Pasterkamp E. et al. Comparison of control and stability of oral anticoagulant therapy using acenocoumarol versus phenprocoumon.. Thromb Haemost 2003; 90: 260-266.
• 10 Barcellona D, Vannini ML, Fenu L. et al. Warfarin or acenocoumarol: which is better in the management of oral anticoagulants?. Thromb Haemost 1998; 80: 899-902.
• 11 Pattacini C, Manotti C, Pini M. A comparative study on the quality of oral anticoagulant therapy (warfarin versus acenocoumarol).. Thromb Haemost 1994; 71: 188-191.
• 12 Hirsh J. Oral anticoagulant drugs.. N Engl J Med 1991; 324: 1865-1875.
• 13 Hemker HC, Frank HL. The mechanism of action of oral anticoagulants and its consequences for the practice of oral anticoagulation.. Haemostasis 1985; 15: 263-270.
• 14 Thijssen HHW, Hamulyák K, Willigers H. 4-Hydroxycoumarin oral anticoagulants: pharmacokineticsresponse relationship.. Thromb Haemost 1988; 60: 35-38.
• 15 Fiessinger JN, Vitoux JF, Roncato M. et al. Variations of prothrombin time, factor VII and protein C with a single dose of acenocoumarol.. Haemostasis 1989; 19: 138-141.
• 16 Mismetti P, Reynaud J, Laporte-Simitsides S. et al. Pharmacokinetic and pharmacodynamic variations of acenocoumarol orally administered either once or twice daily in patients with deep venous thrombosis.. Fundam Clin Pharmacol 1998; 12: 631-635.
• 17 García A, Marín F, Sánchez B. et al. Diurnal variation in the intensity of anticoagulation in atrial fibrillation.. Stroke 2002; 33: 322-324.
• 18 Bleske BE, Welage LS, Warren EW. et al. Variations in prothrombin time and international normalized ratio over 24 hours in warfarin-treated patients.. Pharmacotherapy 1995; 15: 709-712.
• 19 Heneghan C, Alonso-Coello P, Garcia-Alamino JM. et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis.. Lancet 2006; 367: 404-411.
• 20 Van den Besselaar AM, Hoekstra MM. Long-term stability and reproducibility of CoaguChek test strips.. Thromb Haemost 2005; 93: 1189-1192.
• 21 Cromheecke ME, Levi M, Colly LP. et al. Oral anticoagulation self-management and management by a specialist anticoagulation clinic: a randomised cross-over comparison.. Lancet 2000; 356: 97-102.
• 22 Gadisseur APA, Breukink-Engbers WGM, van der Meer FJM. et al. Comparison of the quality of oral anticoagulant therapy through patient self-management and management by specialized anticoagulation clinics the Netherlands.. Arch Intern Med 2003; 163: 2639-2646.
• 23 Kumar S, Haigh JR, Tate G. et al. Effect of warfarin on plasma concentrations of vitamin K dependent coagulation factors in patients with stable control and monitored compliance.. Br J Haematol 1990; 74: 82-85.
• 24 Lind SE, Callas PW, Golden EA. et al. Plasma levels of factors II, VII and X and their relationship to the international normalized ratio during chronic Warfarin therapy.. Blood Coagul Fibrinolysis 1996; 8: 48-53.
• 25 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.
• 26 Kearon C, Kinsberg JS, Kovacs MJ. et al. Extended low-intensity anticoagulation for thromboembolism investigators. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.. N Engl J Med 2003; 349: 631-639.