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Comparison of 5-mg and 10-mg Loading Doses in Initiation of Warfarin Therapy

Linda Harrison, RN; Marilyn Johnston, ART; M. Patricia Massicotte, MD; Mark Crowther, MD; Karen Moffat, ART; and Jack Hirsh, MD

15 January 1997 | Volume 126 Issue 2 | Pages 133-136

Background: Loading doses of warfarin that are larger than those used for maintenance therapy are widely used in clinical practice, but they have never been prospectively evaluated.

Objective: To compare the effect of 5- and 10-mg loading doses of warfarin on laboratory markers of warfarin's anticoagulant effect.

Design: Randomized clinical trial.

Setting: Tertiary care teaching hospital.

Patients: 49 patients seen over a 5-month period with a target international normalized ratio (INR) of 2.0 to 3.0.

Intervention: Patients were randomly assigned to receive an initial dose of 5 or 10 mg of warfarin. Subsequent doses of warfarin were administered on the basis of dosing nomograms.

Measurements: INRs and levels of factors II, VII, IX, and X and protein C were measured daily for 5 days.

Results: 11 of 25 patients in the 10-mg group (44% [95% CI, 34% to 54%]) and 2 of 24 patients in the 5-mg group (8% [CI, 3% to 14%]) had INRs greater than 2.0 at 36 hours (P = 0.005), at which time the factor VII levels were 27% (CI, 18% to 36%) in the 10-mg group and 54% (CI, 43% to 65%) in the 5-mg group (P < 0.001). In contrast, factor II levels were 74% (CI, 67% to 81%) in the 10-mg group and 82% (CI, 73% to 93%) in the 5-mg group (P > 0.2). At 60 hours, 9 of 25 patients in the 10-mg group (36% [CI, 17% to 54%]) and no patients in the 5-mg group had INRs greater than 3.0. At 84 hours, 15 of 24 patients in the 10-mg group (63% [CI, 43% to 81%]) and 19 of 24 patients in the 5-mg group (79% [CI, 62% to 95%]) had INRs between 2.0 and 3.0. Four patients in the 10-mg group and 1 patient in the 5-mg group received vitamin K for excessive prolongation of the INR.

Conclusions: A 5-mg loading dose of warfarin produces less excess anticoagulation than does a 10-mg loading dose; the smaller dose also avoids the development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hours of warfarin therapy.

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Warfarin levels are monitored by measuring the prothrombin time, which responds to reductions in levels of three vitamin K-dependent clotting factors: factors II, VII, and X [1, 2]. During the first 48 hours of treatment, the anticoagulant effect of warfarin is caused mainly by a reduction in the activity of factor VII, which has a half-life of 6 hours. In contrast, the antithrombotic effect of warfarin (which is thought to be caused primarily by a reduction in the activity of factor II) is delayed for as long as 60 hours [3, 4]. Therefore, during the first 48 hours of therapy, the anticoagulant and antithrombotic effects of warfarin may be dissociated. In addition, because the half-life of the vitamin K-dependent anticoagulant protein, protein C, is similar to that of factor VII [5], the early anticoagulant effect of warfarin (which results from reduction of factor VII) could be counteracted by a procoagulant effect (which results from reduction of protein C) [6].

Warfarin treatment is often initiated with a 10-mg loading dose and then reduced to a level that maintains the international normalized ratio (INR) within the therapeutic range. An alternative approach is to start warfarin therapy at a dose of 5 mg, which is the average dose required to maintain an INR of 2.0 to 3.0. Although a 10-mg loading dose produces a more rapid increase in the prothrombin time, this effect is caused largely by a decrease in factor VII levels and therefore may not produce a more rapid antithrombotic effect.

The 10-mg loading dose has three potential short-comings. First, if heparin is discontinued as soon as the INR reaches the therapeutic range, thrombus extension may occur. This is because the antithrombotic effect of warfarin may not yet have manifested. Second, elderly or vitamin K-deficient patients may be exposed to an unnecessary risk for bleeding [7-12]. Third, protein C levels can be excessively decreased before the full antithrombotic effect of warfarin has been completely expressed through the reduction of factor II.

On the basis of these considerations, we did a study to compare the relative effects of 5- and 10-mg loading doses of warfarin on four surrogate laboratory markers of efficacy and safety.

Methods

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Patients with no contraindications to warfarin who required anticoagulation (target INR, 2.0 to 3.0) were invited to participate in the trial between June and November 1994 at The Hamilton Civic Hospitals (Ontario, Canada). Enrollment was targeted at 50 patients. All patients gave written, informed consent, and the study was approved by the local internal review board.

Patients were assigned by random number Table to receive warfarin at an initial dose of 5 or 10 mg. Subsequent doses were determined on the basis of nomograms that were developed before the study began through an iterative process. Because the study used laboratory outcomes, patients and health care professionals were not blinded to treatment assignments.

Patients were followed for a maximum of 108 hours, during which time they received five doses of warfarin. Blood samples were taken before warfarin therapy was initiated, 12 hours after the first dose of warfarin, and at 24-hour intervals for 5 days. Blood was collected into vacuum-sealed containers that contained 0.102 mol of buffered sodium citrate per liter. To obtain platelet-free plasma, the sample was double centrifuged at 1700 g and frozen at –70°C for batch assays [13].

The prothrombin time was measured using Thromborel S (International Sensitivity Index 1.06, Behring Diagnostics, Kanata, Ontario, Canada) and reported as an INR [14]. Heparin does not increase the prothrombin time in patients receiving both warfarin and heparin if this thromboplastin reagent is used. Factors II, VII, IX, and X were assayed by using the one-stage clotting method [15]. Protein C levels were measured by using a functional clotting assay (Dade International, Mississauga, Ontario, Canada) [16]. Treatment of supratherapeutic INRs with vitamin K was left to the discretion of the attending physician.

The outcome measures were the time required to achieve an INR of 2.0 to 3.0, the proportion of INR values greater than 3.0, the time course for reductions in levels of factors II and X, and the time course for reduction in protein C levels. Additional data included levels of factors VII and IX.

Results

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Fifty-one consecutive patients were enrolled in the trial. Two were excluded after one dose of warfarin: One died, and one required cardiac catheterization. Twenty-five patients were randomly assigned to receive a 10-mg loading dose of warfarin; 24 were assigned to receive a 5-mg loading dose. The two groups did not differ in age; weight; or frequency of acute thromboembolism, cancer, or surgery during or immediately before the study period. Forty-eight patients received concomitant heparin therapy for all or part of the study period.

Beginning on study day 2, the dose of warfarin was adjusted using a nomogram. Warfarin doses in the two groups were similar except on days 1 and 2. The 10-mg group achieved an INR greater than 2.0 statistically significantly sooner than did the 5-mg group (Table 1). At 36 hours, 11 of 25 patients (44% [CI, 34% to 54%]) in the 10-mg group had INRs of 2.0 or greater compared with 2 of 24 patients (8% [CI, 3% to 14%]) in the 5-mg group (P = 0.005). At 60 hours, 9 of 25 patients in the 10-mg group (36% [CI, 17% to 54%]) had INRs greater than 3.0 compared with none of 23 patients in the 5-mg group (P = 0.002). Five patients (4 in the 10-mg group and 1 in the 5-mg group) received vitamin K. These patients had INRs of 4.8 to 9.3 and received 0.5 to 2.0 mg of vitamin K subcutaneously. No patient bled.

View this table: [in this window] [in a new window]   Table 1. International Normalized Ratios for Patients Assigned to Receive a 5- or 10-mg Loading Dose of Warfarin*

 

Levels of factors II and X declined slowly, and no substantial differences were seen between the 5-and 10-mg groups. In contrast, levels of factor VII and protein C decreased more rapidly and were statistically significantly lower in the 10-mg group than in the 5-mg group at 36 and 60 hours (Figure 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. Plasma levels of coagulation factors in patients receiving a 10-mg (striped bars) or 5-mg (white bars) loading dose of warfarin for each of six time points assessed. Levels of factor II (top) decreased at a similar rate in the 5- and 10-mg groups. Levels of factor VII (middle) and protein C (bottom) decreased more rapidly in the 10-mg group than in the 5-mg group. Error bars represent 95% Cls.

 

Discussion

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We compared the relative effects of 5- and 10-mg loading doses of warfarin. The time course of reduction in levels of factor II was used as a surrogate end point for clinical efficacy, and excessive elevation of the prothrombin time and unopposed reduction in protein C levels were used as surrogate end points for safety.

Patients who received a 10-mg loading dose of warfarin achieved INRs greater than 2.0 more rapidly than did patients who received a 5-mg loading dose. However, because this change in the INR was entirely caused by the early reduction of factor VII levels in the 10-mg group, it may not reflect an antithrombotic effect of warfarin, which is thought to result from a reduction in factor II levels. Two separate experimental observations in rabbits support this idea: The first is the early report of a 5-day delay in achieving an antithrombotic effect with warfarin, although the prothrombin time was first prolonged into the therapeutic range and the level of factor VII was markedly reduced after 2 days of treatment [17]. This observation provides the rationale for overlapping heparin and warfarin therapy for 5 days during the initiation of anticoagulant therapy [17, 18]. The second is the finding that the antithrombotic effect of warfarin is abrogated by the infusion of factor II and (to a lesser extent) factor X [18]. In our study, the rate of reduction in levels of factor II and factor X activity were similar in the 5- and 10-mg groups.

On the other hand, the 10-mg loading dose was associated with a significantly more rapid decrease in protein C activity (which decreased before levels of factors X and II were substantially reduced) than that seen in the 5-mg group and an excessive prolongation of the INR. The combination of markedly reduced protein C levels and near-normal levels of factors II and X over the first 2 days of warfarin therapy could produce a hypercoagulable state, and excessive prolongation of the INR could create a higher risk for bleeding.

Our study is limited because we used surrogate markers for efficacy and safety. A much larger trial using clinical outcome measures is needed to determine whether the surrogate markers that we used are clinically relevant. Nevertheless, our findings suggest that both regimens result in a therapeutic INR in most patients by day 5 of treatment.

From Hamilton Civic Hospital, McMaster University, and The Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.

Author and Article Information

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For author affiliations and current author addresses, see end of text.
Grant Support: In part by the Heart and Stroke Foundation of Canada, the Medical Research Council of Canada, and DuPont Pharmaceuticals, USA.
Requests for Reprints: Jack Hirsh, MD, The Hamilton Civic Hospitals Research Centre, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.
Current Author Addresses: Ms. Harrison; Ms. Johnston; Drs. Massicotte, Crowther, and Hirsh; and Ms. Moffat: The Hamilton Civic Hospitals Research Centre, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

References

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2. Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants. Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 1995; 108(4 Suppl):231S-46S.

3. Hellemans J, Vorlat M, Verstraete M. Survival time of prothrombin and factors VII, IX, X after complete synthesis blocking doses of coumarin derivatives. Br J Haematol. 1963; 9:506-12.

4. Roberts HR, Lechler E, Webster WP, Penick GD. Survival of transfused factor X in patients with Stuart disease. Thrombosis et Diathesis Haemorrhagica. 1965; 13:305-9.

5. Vigano S, Mannucci PM, Solinas S. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy. Br J Haematol. 1984; 57:213-20.

6. Okajima K, Koga S, Kaji M, Inoue M, Nakagaki T, Funatsu A, et al. Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects. Thromb Haemost. 1990; 63:48-53.

7. Hull RD, Hirsh J, Jay R, Carter C, England C, Gent M, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med. 1982; 307:1676-81.

8. Turpie AG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet. 1988; 1:1242-5.

9. Saour JN, Sieck JO, Mamo LA, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med. 1990; 322:428-32.

10. Altman R, Rouvier J, Gurfinkel E, D'Ortencio O, Manzanel R, de La Fuente L, et al. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg. 1991; 101:427-31.

11. Landefeld CS, Rosenblatt MW. Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions. Am J Med. 1989; 87:153-9.

12. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989; 87:144-52.

13. Johnston M, Harrison L, Moffat K, Willan A, Hirsh J. Reliability of the INR for monitoring the induction phase of warfarin: comparison with the prothrombin time ratio. J Lab Clin Med. 1996; 128:214-7.

14. WHO Expert Committee on Biological Standardization. Thirty-third report. World Health Organ Tech Rep Ser. 1983; 687:81-105.

15. Bigg R. Human Blood Coagulation. London: Blackwell Scientific; 1972:614.

16. Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest. 1981; 68:1370-3.

17. Wessler S, Gitel SN. Warfarin. From bedside to bench. N Engl J Med. 1984; 311:645-52.

18. Zivelin A, Rao LV, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors. J Clin Invest. 1993; 92:2131-40.

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