A randomized trial of initial warfarin dosing based on simple clinical criteria

Summary

Warfarin induction is accomplished by titrating dosage to coagulation test results. Algorithms can guide this process but not identify the starting dose. We hypothesized that an initial warfarin dose approximating the maintenance value would safely enhance rapidity of induction. In a randomized trial we compared a fixed-dose to a maintenance-dose strategy for beginning warfarin therapy. To predict the maintenance dose among patients with differing warfarin requirements we performed regression analysis on clinical factors derived from chart review. Four community hospitals supplied records for retrospective analysis. The prospective trial was conducted in one, a 350-bed teaching institution. A sample of inpatients anti-coagulated during 1998 formed the development set for retrospective study; a 1999 sample formed the validation set. A one-year trial recruited consecutive eligible inpatients initiated on warfarin. We randomly assigned patients to a first warfarin dose calculated using our regression formula or fixed at 5 mg. All patients’ subsequent doses were determined (as a percentage of initial) from coagulation testing. We compared days to anticoagulation, hospitalized hours, complications, and activity of factor II and protein C in a patient sample at intervals after induction. Weight, age, serum albumin, and presence of malignancy explained 25-30% of variance in maintenance dose. Ninety patients (44 calculated-dose and 46 standard-dose) evaluated in the clinical trial. Mean time to anticoagulation (among patients achieving anticoagulation) was 4.2 and 5.0 days, respectively (p = 0.007). We observed no significant differences in other endpoints. Individualized initial dosing may safely hasten war-farin induction.

Keywords

Warfarin - randomized trials - dosing algorithms

• References

• 1 Oates A, Jackson PR, Austin CA, Channer KS. A new regimen for starting warfarin therapy in outpatients. Br J Clinical Pharmacol 1998; 46 (02) 157-61.
• 2 Fennerty A, Dolben J, Thomas P, Backhouse G, Bentley DP, Campbell IA, Routledge PA. Flexible induction dose regimen for warfarin and prediction of maintenance dose. BMJ 1984; 1268-70.
• 3 White RH, Hong R, Venook AP, Daschbach MM, Murray M, Mungall DR, Coleman RW. Initiation of warfarin therapy. J Gen Intern Med 1987; 2: 141-8.
• 4 Ryan PJ, Gilbert M, Rose PE. Computer control of anticoagulation dose for therapeutic management. BMJ 1989; 1207-9.
• 5 Poller L, Shiach CR, MacCallum PK, Johansen AM, Munster AM, Magalhaes A, Jespersen J. Multicenter randomised study of computerised anticoagulant dosage. Lancet 1998; 352: 1505-9.
• 6 Fredriks DA, Coleman RW. Nomogram for dosing warfarin at steady state. Clin Pharmacy 1991; 10: 923-7.
• 7 Svec JM, Coleman RW, Mungall DR, Ludden TM. Bayesian pharmacokinetic/pharmacodynamic forecasting of prothrombin response to warfarin therapy: preliminary evaluation. Ther Drug Monit 1985; 7: 174-80.
• 8 Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J. Comparison of 5-mg and 10-mg Loading Doses in Initiation of warfarin therapy. Ann Intern Med 1997; 126: 133-6.
• 9 Horton JD, Bushwick BM.. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician 1999; 59: 635-46.
• 10 Gugliemone HA, Vides MA.. A novel functional assay of protein C in human plasma and its comparison with amidolytic and anticoagulant assays, Thromb Heamost. 1992; 67: 46-9.
• 11 Woodhams B, Giardot O, Blanco MJ, Colesse G, Gourmelin Y. Stability of coagulation proteins in frozen plasma. Blood Coagul Fibrinolysis 2001; 12: 229-36.
• 12 Fihn SD, McDonell M, Martin D, Henikoff J, Vermes D, Kent D, White RH. and the Warfarin Optimized Outpatient follow-up Study Group. Risk factors for complications of chronic anticoagulation. Ann Inter Med 1993; 118: 511-20.
• 13 Coppleston A, Roath S. Assessment of Therapeutic control of anticoagulation. Acta Haematol 1984; 76: 376-80.
• 14 Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994; 121: 676-83.
• 15 Hulse ML.. Warfarin resistance: diagnosis and therapeutic alternatives. Pharmacotherapy 1996; 16: 1009-17.
• 16 Alving BM, Strickler MP, Knight RD, Barr CF, Berenberg JL, Peck CC. Hereditary war- farin resistance. Arch Intern Med 1985; 145: 499-501.
• 17 Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1995; 108 (Suppl. 04) Supp4 231S-246S.
• 18 Vadher B, Patterson DLH, Leaning M. Evaluation of a decision support system for initiation and control of oral anticoagulation in a randomised trial. BMJ. 1997: 1252-6
• 19 Reitsma PH. Protein C deficiency: from gene defects to disease. Thromb Haemost 1997; 78: 344-50.
• 20 White RH, Zhou H, Romano P, Mungall D. Changes in plasma warfarin levels and variations in steady-state prothrombin times. Clin Pharmacol Therap 1995; l38: 588-93.
• 21 Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction of factors known at the start of therapy. Am J Med 1989; 87: 144-52.