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Frequently Asked Questions

Warfarin, to load or not to load?

Warfarin is an oral anticoagulant frequently used to treat or prevent various thromboembolic events or diseases associated with substantial risk of thromboembolism.

In 2001, it was listed among the top 100 selling prescription drugs in the United States. Despite this volume of prescription sales, there remains confusion about the appropriate management of warfarin dosing, particularly in regards to initiating patients na´ve to oral anticoagulant therapy. Discrepancies exist in clinical practice on initiation of warfarin therapy utilizing a loading dose (10 mg or greater for 2 or more days) versus initiation at average daily maintenance doses (5 mg). This may be due to a lack of understanding about warfarin's pharmacology or mechanism of action and to the limited published literature that addresses this issue.

Warfarin works through antagonism of the vitamin K oxidation system. The liver uses oxidized vitamin K in the synthesis of clotting factors VII, IX, X and II. This interference with vitamin K oxidation results in an inhibition of the factor synthesis process and anticoagulation is ultimately achieved after clearance of the currently active clotting factors occurs. The half-life of activated clotting factors varies from 6 hours (factor VII) to 50 hours (factor II). This means that initial changes in the international normalized ratio (INR) can be seen in as little as 24-36 hours, with depletion of activated factor VII, and full antithrombotic effects are seen in 5-7 days, as activated factor II is depleted.

Warfarin has both anticoagulant and antithrombotic properties. Anticoagulation is achieved when therapeutic INRs are attained (an INR between 2-3 is considered therapeutic in most instances), which can occur within 1-3 days after therapy initiation. However, recall that these changes reflect depletion of Factor VII. This means that sufficient concentrations of activated Factor IX, X and II remain and are able to propagate clot formation. The ability of warfarin to inhibit clot expansion or development, or its antithrombotic effect, is achieved after clearance of Factor II (prothrombin). Thus, therapeutic INRs within the first few days after warfarin initiation do not equal clinical effectiveness, particularly in the case of management of acute thromboembolic events. This delayed effect on prothrombin is the reason for concomitant heparin therapy during the first 4-5 days of warfarin therapy regardless of attainment of a therapeutic INR.

In addition to synthesis of clotting factors, oxidized vitamin K is used in the production of proteins C and S, our endogenous anticoagulants. Thus, warfarin therapy also inhibits production of these proteins. Protein C has a half-life of only about 8 hours and is there fore depleted rather quickly after initiation of warfarin therapy. This in turns leads to the development of a hypercoaguable state resultant from this depletion of endogenous anticoagulants with persistent activity of endogenous clotting factors.

Theoretically, initiating warfarin with loading doses of 10 mg per day or more should lead to INR values within the therapeutic range more quickly than daily doses of 5 mg. This may very well be the case, and in fact, this does often occur, but we know that therapeutic INRs within the first few days of warfarin therapy do not translate into clinical effectiveness for antithrombosis. In addition, using loading doses of warfarin could potentiate hypercoaguability with rapid effects on proteins C and S. The full effects of loading doses will not be observed until days 5-7 after initiation. This means that a therapeutic INR on day 2 could be a supratherapeutic INR (> 3.0 or >3.5 depending on indication) on day 5 and may put the patient at increased risk for bleeding complications. Some studies have been published in the medical literature that addresses this question.

In the late 1960's, O'Reilly and colleagues examined the effects of weight based loading doses of warfarin (1.5 mg/kg of body weight), compared to once daily doses of 10 or 15 mg, on prothrombin time and plasma concentrations of factors VII, IX, X, and II. Thirty- two otherwise healthy subjects were given a one time loading dose of 1.5 mg/kg and observed for 120 hours. The average warfarin dose administered was about 100 mg. Effect on prothrombin time was reported as a percentage of normal prothrombin complex activity. A therapeutic range was considered to be <35% of normal activity. By 36 hours, all subjects had prothrombin complex activity <35% of normal with maximal effects seen at 48 hours that persisted throughout the observation period. In a second series of study the same population was divided into 2 groups of 15 subjects each and received either 10 or 15 mg of warfarin a day. These subjects were observed for at least 120 hours. In the 10 mg per day group, the mean prothrombin complex activity was 36% of normal by day 5 and 32% of normal by day 6. In the 15 mg per day group, mean activity fell to 28% of normal by day 4. The authors then concluded that a single weight based loading dose of warfarin lead to therapeutic effects on prothrombin time significantly more quickly than either the 10 or 15 mg per day doses. However, when comparing the effect on percent change in plasma clotting factors in 6 subjects they found that there was only a statistically significant difference in the change of Factor VII at 24 and 48 hours. Percent change in concentration of Factors IX, X, and II were similar for both the groups receiving the 1.5 mg/kg dose or the 15 mg/day dose at all time periods of observation. This then appears that the more rapid changes seen in prothrombin complex activity may be related to decreased concentrations of Factor VII and not to changes in Factor IX, X, or II. Therefore the question still remains whether or not this large load produces a clinically significant therapeutic response at 36 hours.

Harrison and colleagues conducted a randomized clinical trial to compare the effects of 5 and 10 mg loading doses of warfarin. They used laboratory markers (time to reduction in levels of Factor II and X, and protein C) as indicators of both safety and efficacy. Other outcome measures included time needed to reach INR values in the therapeutic range (2.0-3.0) and percentage of supratherapeutic INRs (>3.0). Fifty-one patients were enrolled and randomly assigned to receive either 5 or 10 mg warfarin loading doses for the first 2 consecutive days of therapy. After that time, warfarin dosing was adjusted using a nomogram. The 2 groups were similar in respect to baseline characteristics with 25 and 24 people in the 10 mg and 5 mg groups, respectively. There was a statistically significantly greater number of people in the 10 mg group with therapeutic INRs (>2.0) at 36 hours as compared to the 5 mg group (44% vs. 8% respectively, P = 0.005). However, at 60 hours none of the persons in the 5 mg group had supratherapeutic INRs, which was significantly less than in the 10 mg group (36%, P = 0.002). There were no bleeding events noted for either group. Similar to the findings by O'Reilly, levels of Factor II and X gradually decreased with no significant differences between the groups; while Factor VII and protein C levels decreased quickly and were significantly lower in the 10 mg group at both 36 and 60 hours. These findings do not support the use of loading doses of 10 mg or more as antithrombotic effects were reached in similar periods in both groups despite quicker attainment of a therapeutic INR in the 10 mg group.

Another group of investigators, headed by Crowther, also compared effects of 5 and 10 mg loading doses of warfarin in a prospective, randomized clinical trial. Their goal was to assess the ability of the dosing strategies to achieve a stable INR between 2.0-3.0 within the first 5 days of therapy. The primary endpoint was the proportion of people with therapeutic INR values for 2 consecutive days and whose INR did not exceed 3.0. Like patients in Harrison's study, these patients received the loading doses on days 1 and 2 and thereafter dosing was adjusted using an algorithm. Fifty-three persons were enrolled (32 in the 5 mg group, 21 in the 10 mg group). A larger percentage of people in the 5 mg group reached the primary endpoint (66%) as compared to the 10 mg group (24%, P <0.003). Additionally, there was a greater incidence of supratherapeutic INRs (>3.0) by study day 4 in the 10 mg group (24% vs. 7%, P = 0.11).

These studies share one common limitation, small sample size. Also, in none of the studies do the authors comment on whether or not their studies were designed with sufficient power to detect the differences that they did between groups. However, when considering that similar results were seen in these trials, for both INR outcomes and change in levels of clotting factors, they do offer some evidence to help answer our question regarding warfarin loading and support the current Chest Guideline recommendation. This recommendation is that initiation of warfarin using loading doses is unnecessary as a therapeutic INR can be achieved in 4-5 days in most cases when beginning with 5 mg a day dosing. In addition, keep in mind that certain patients may be more sensitive to the effects of warfarin, like those with liver disease, malnutrition, or the elderly. These patients may even require initial doses less than 5 mg per day. Also, it is prudent to comment that persons with a history of warfarin use with higher than average maintenance dosing requirements may need initiation at doses greater than 5 mg per day in order to achieve effective antithrombosis in a reasonable time frame.

References:

  1. RxList. The top 200 prescriptions for 2001 by number of US prescriptions dispensed. Available at http://www.rxlist.com/top200.htm. Accessed May 2002.


  2. Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician 1999 Feb;59(3):635-46.


  3. Gage BF, Fihn SD, White RH. Management and dosing of warfarin. Am J Med 2000 Oct;109(6):481-8.


  4. O'Reilly RA, Aggeler PM. Studies on coumarin anticoagulant drugs. Circulation 1968 July; 38(1):169-77.


  5. Harrison L, Johnston M, Massicotte PM, Crowther M, Moffat K, Hirsh, J. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997 Jan;126(2):133-6.


  6. Crowther M, Ginsberg JB, Kearon C, Harrison L, Johnson J, Massicotte PM, et al. A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 1999 Jan;159(1):46-8.


  7. Ansell J, Hirsh J, Dalen J, Bussey H, Anderson D, Poller L, et al. Managing oral anticoagulant therapy. Chest 2001 Jan;119(1 Suppl):22S-38S.

 

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