Anticoagulant and antithrombotic effects may be dissociated in the first days of treatment
4-15 COMPARISON OF 5-MG AND 10-MG LOADING DOSES IN INITIATION OF WARFARIN THERAPY
The prothrombin time responds to reduction in levels of 3 vitamin-K dependent clotting factors: factors II, VII, and X. 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. Therefore, during the first 48 hours of therapy, the anticoagulant and antithrombotic effects of warfarin may be dissociated.
Protein C is also a vitamin-K dependent anti-coagulant factor. It has a half life similar to that of factor VII. Thus, the early anti-coagulant effect of warfarin (which results from reduction of factor VII) could be counteracted by a pro -coagulant effect due to a reduction in protein C.
Warfarin treatment is often initiated with a 10-mg loading dose and then reduced to a level that maintains the INR within the therapeutic range. An alternative approach is to start warfarin at a dose of 5 mg (the average dose required to maintain the INR at 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 dose has three potential short comings: 1) If heparin is discontinued as soon as the INR reaches the therapeutic range, thrombus extension may occur because the antithrombotic effect of warfarin may not yet have manifested; 2) Elderly or vitamin K-deficient patients may be exposed to unnecessary risk for bleeding; 3) 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, this study compared the relative effects of 5-and 10-mg loading doses of warfarin.
Conclusion: A 5-mg loading dose produces far less anti--coagulation than a 10-mg dose and avoids the development of a potential hyper--coagulable state caused by the precipitous decreases in levels of protein C.

STUDY

1. Randomized clinical trial of 49 patients with a target INR of 2.0 to 3.0.
2. Half received a 5-mg loading dose; half a 10-mg loading dose.
3. Almost all patients received concomitant heparin. (The thromboplastin used for measuring INR had an international sensitivity index of 1.06. Heparin does not increase the prothrombin time in patients receiving both heparin and warfarin if this special thromboplastin reagent is used.)
4. Beginning on day 2, the dose of warfarin was adjusted using a nomogram.

RESULTS

1. The 10-mg group achieved an INR greater than 2.0 significantly sooner than did the 5-mg group.
2. At 60 hours, one third of the 10-mg group had INRs greater than 3.0 vs none in the 5-mg group.
3. Levels of factor II and X declined slowly, with no substantial differences between the 2 groups.
4. In contrast, levels of factor VII and protein C decreased more rapidly and were significantly lower in the 10-mg group at 36 and 60 hours.
5. At 8-h, 63% of the 10-mg group and 79% of the 5-mg group had INRs 2.0 to 3.0.

DISCUSSION

1. The time course of reduction in factor II was used as a surrogate end point for clinical efficacy.
2. Excessive elevations of the prothrombin time and unopposed reductions in protein C levels were used a surrogate end points for safety.
3. Patients receiving a 10-mg loading dose achieved INRs greater than 2.0 more rapidly than those receiving a 5-mg dose. However, because this change in the INR was caused by the early reduction in 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.
4. This provides a rationale for overlapping heparin and warfarin therapy for 5 days during the initiation of anticoagulant therapy.
5. The rate of reduction of factor II and factor X activity were similar in the 5- and 10-mg groups.
6. 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. The 10 mg dose produced an excessive prolongation of the INR.
7. 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 hyper-coagulable state. The excessive prolongation of the INR could create a higher risk of bleeding.
8. "Our study is limited because we used surrogate markers for efficacy and safety. A much larger clinical trial is needed to determine if these surrogate markers are clinically relevant."

CONCLUSION
A 5-mg loading dose of warfarin produced less excess anticoagulation than did a 10-mg loading dose; the smaller dose also avoided development of a potential hypercoagulable state caused by precipitous decreases in levels of protein C during the first 36 hours of warfarin therapy.
Annals Int. Med. January 15, 1997: 126: 133-36 Original investigation from McMaster Univ. Hamilton, Ontario, Canada

Comment:
This is a new concept to me. During initiation of warfarin therapy the trick is to avoid higher doses. This can have 2 adverse effects in the first 2 days:

1) Risk of over anticoagulation—and possibility of bleeding. (In this study the INR at 5 days exceeded 3.0 in many patients receiving the 10-mg dose, but in none receiving 5.)

2) Risk of thrombosis due to reduction in levels of protein C, a natural anticoagulant.

The protective effect of warfarin is due primarily to reduction in factor II levels. There is no benefit in hastening to increase the INR rapidly with warfarin since reduction in factor II levels does not occur within the first 2 days. RTJ

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