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Original article

Vol. 143 No. 0102 (2013)

Randomised trial of a clinical dosing algorithm to start anticoagulation with phenprocoumon

  • Angela Caduff Good
  • Daniel Nobel
  • Stephan Krähenbühl
  • Christof Geisen
  • Samuel Henz
DOI
https://doi.org/10.4414/smw.2013.13709
Cite this as:
Swiss Med Wkly. 2013;143:w13709
Published
30.12.2012

Summary

QUESTION UNDER STUDY: Prospective validation of two algorithms for the initiation of phenprocoumon treatment.

METHODS: Inpatients with new-onset anticoagulation were randomised to one of two computer assisted dosing algorithms, or to a control arm. The primary outcome measure was the time to achieve therapeutic anticoagulation without overshooting (INR >4.0 within 10 days). Secondary outcomes included overshooting INR values, death, or bleeding within 30 days. In addition, predictors of the dosing algorithms for the loading dose and the maintenance dose including genetic parameters were reassessed.

RESULTS: 105 patients were randomised to arm A, 103 to arm B and 93 to the control arm. Arms A and B needed a median of 7 days to reach a therapeutic INR, arm C 6 days (p = 0.5). Overshooting INR was observed in 3.8%, 1.9% and 4.3% respectively (p = 0.6). Bleeding was found in 0%, 1.9%, and 5.4% (p = 0.06) and 30-day mortality was 0%, 1%, and 2.2% respectively (p = 0.2). VKORC1:c.-1639 G>A was associated with lower loading doses whereas VKORC1:c.-1453 G>A needed higher doses. VKORC1:c.-1639 G>A was also associated with lower maintenance doses.

CONCLUSION: Both algorithms allow safe initial dosing of phenprocoumon but they are not superior to anticoagulation by trained physicians. Dosing aids for coumarins with readily available clinical parameters may nevertheless be helpful for use in polymorbid hospitalised patients. Clinical data and the INR-response to treatment provides powerful information and delaying initiation of anticoagulation while awaiting genetic tests is not expected to increase drug safety.

References

  1. 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(7):492–501.
  2. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 2001;119(1 Suppl):8–21S.
  3. Stein PD, Alpert JS, Bussey HI, Dalen JE, Turpie AG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest. 2001;119(1 Suppl):220S–7S.
  4. Ufer M. Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet. 2005;44(12):1227–46.
  5. Hemker HC, Frank HL. The mechanism of action of oral anticoagulants and its consequences for the practice of oral anticoagulation. Haemostasis. 1985;15(4):263–70.
  6. Kelly JG, O’Malley K. Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet. 1979;4(1):1–15.
  7. Beinema M, Brouwers JR, Schalekamp T, Wilffert B. Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon. Thromb Haemost. 2008;100(6):1052–7.
  8. Becquemont L. Evidence for a pharmacogenetic adapted dose of oral anticoagulant in routine medical practice. Eur J Clin Pharmacol. 2008;64(10):953–60.
  9. Meyer zu Schwabedissen C, Mevissen V, Schmitz F, Woodruff S, Langebartels G, Rau T, et al. Obesity is associated with a slower response to initial phenprocoumon therapy whereas CYP2C9 genotypes are not. Eur J Clin Pharmacol. 2006;62(9):713–20.
  10. Tanaka E. In vivo age-related changes in hepatic drug-oxidizing capacity in humans. J Clin Pharm Ther. 1998;23(4):247–55.
  11. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther. 1997;61(3):331–9.
  12. Oldenburg J, Watzka M, Rost S, Muller CR. VKORC1: molecular target of coumarins. J Thromb Haemost. 2007;5(Suppl 1):1–6.
  13. Luxembourg B, Schneider K, Sittinger K, Toennes SW, Seifried E, Lindhoff-Last E, et al. Impact of pharmacokinetic (CYP2C9) and pharmacodynamic (VKORC1, F7, GGCX, CALU, EPHX1) gene variants on the initiation and maintenance phases of phenprocoumon therapy. Thromb Haemost. 2011;105(1):169–80.
  14. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):160S–98S.
  15. Arnold ML, Grond-Ginsbach C, Kloss M, Di Mascio MT, Veltkamp R, Ringleb P, et al. Pharmacogenetic testing for guiding de novo phenprocoumon therapy in stroke patients. Cerebrovasc Dis. 2009;28(5):468–71.
  16. Geisen C, Luxembourg B, Watzka M, Toennes SW, Sittinger K, Marinova M, et al. Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters. Eur J Clin Pharmacol. 2011;67(4):371–81.
  17. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 – rationale and perspectives. Thromb Res. 2007;120(1):1–10.
  18. Schalekamp T, Brasse BP, Roijers JF, van Meegen E, van der Meer FJ, van Wijk EM, et al. VKORC1 and CYP2C9 genotypes and phenprocoumon anticoagulation status: interaction between both genotypes affects dose requirement. Clin Pharmacol Ther. 2007;81(2):185–93.
  19. Visser LE, van Vliet M, van Schaik RHN, Kasbergen AAH, De Smet PAGM, Vulto AG, et al. The risk of overanticoagulation in patients with cytochrome P450CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics. 2004;14(1):27–33.
  20. Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005;352(22):2285–93.
  21. Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Frye-Anderson A, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358(10):999–1008.
  22. Schalekamp T, Oosterhof M, van Meegen E, van Der Meer FJ, Conemans J, Hermans M, et al. Effects of cytochrome P450 2C9 polymorphisms on phenprocoumon anticoagulation status. Clin Pharmacol Ther. 2004;76(5):409–17.
  23. Werner D, Werner U, Wuerfel A, Grosch A, Lestin HG, Eschenhagen T, et al. Pharmacogenetic characteristics of patients with complicated phenprocoumon dosing. Eur J Clin Pharmacol. 2009;65(8):783–8.
  24. Good AC, Henz S. A clinical algorithm to predict the loading dose of phenprocoumon. Thromb Res. 2007;120(6):921–5.
  25. Geisen C, Watzka M, Sittinger K, Steffens M, Daugela L, Seifried E, et al. VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb Haemost. 2005;94(4):773–9.
  26. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007;116(22):2563–70.
  27. Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008;84(3):326–31.
  28. Gong IY, Tirona RG, Schwarz UI, Crown N, Dresser GK, Larue S, et al. Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood. 2011;118(11):3163–71.
  29. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008;83(3):460–70.
  30. International Warfarin Pharmacogenetics C, Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360(8):753–64.
  31. Millican EA, Lenzini PA, Milligan PE, Grosso L, Eby C, Deych E, et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood. 2007;110(5):1511–5.
  32. Milligan G, Gage, Eby, Gatchel, Deych, King. WARFARINDOSING. Oct 30, 2011 [cited 2012]; Available from: http://www.warfarindosing.org/Source/Home.aspx.
  33. Qazim B, Stollberger C, Krugluger W, Dossenbach-Glaninger A, Finsterer J. Dependency of phenprocoumon dosage on polymorphisms in the VKORC1 and CYP2C9 genes. J Thromb Thrombolysis. 2009;28(2):211–4.
  34. Gage BF. Pharmacogenetics-based coumarin therapy. Hematology Am Soc Hematol Educ Program. 2006:467–73.

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