Among the current controversies regarding is the issue of dosing in the first few days, or the “loading phase” of therapy. Over the last 10 to 20 years, clinicians have moved away from the loading doses of 10 to 50 mg in favor of less aggressive “front-loading.”
Harrison et al. compared the effects of single loading doses of warfarin 5 mg and 10 mg in a randomized clinical trial. They examined the time to reduction in levels of factor II and X, as well as protein C, as indicators of both efficacy and safety. They also measured the time needed to reach therapeutic INR values (2 to 3). Their results showed a significantly greater number of patients in the 10-mg group with supratherapeutic INRs. Levels of factor II and factor X gradually decreased with no significant difference between the two groups, but factor VII and protein C levels decreased quickly and were much lower in the 10-mg group at 36 and 60 hours. These findings suggested that despite the faster attainment of a therapeutic INR, the use of a 10-mg loading dose was not recommended.
In a trial by Crowther et al., the primary endpoint was the proportion of patients with therapeutic INR values for two consecutive days and whose INRs did not exceed 3.0. Patients received either a 5-mg or a 10-mg dose of warfarin for the first day, after which an algorithm was used to adjust the dosing. More patients receiving 5 mg were able to reach their target INRs than patients receiving 10 mg. In addition, more patients in the 10-mg group reached supratherapeutic levels.
In a study that reached the opposite conclusions of the previous two, Kovacs et al. compared a single 10-mg initiation-dose nomogram with a 5-mg nomogram in a randomized, controlled clinical trial; they found the loading dose to be of some benefit. The primary endpoint was the number of days needed to achieve a therapeutic INR. Patients in the 10-mg group achieved therapeutic INRs 1.4 days earlier than patients in the 5-mg group (P < .001). By the “magic” fifth day, 83% of patients receiving 10 mg had achieved a therapeutic INR, in contrast to only 46% of the patients receiving 5 mg (P < .001). There were no significant differences in recurrent thrombo-embolic events, in major bleeding, in 90-day survival, or in the number of INRs above 5 in the two groups.
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One plausible explanation for the more favorable loading dose results in the Kovacs study was that the subject population consisted entirely of outpatients. Outpatients are generally healthier and younger and are taking fewer medications than their inpatient counterparts. In fact, in a previous study, Kovacs et al. concluded that hospitalized patients were generally more sensitive to warfarin than outpatients. Therefore, inpatients might be less in need of the higher loading dose in order to attain the most efficient anticoagulant regimen.
Thus, from the composite of these three studies, the ability of front-loading regimens to help attain target INRs more safely and efficiently appears to be inconsistent at best; larger, well-designed studies are still needed to further clarify this issue. At present, perhaps higher “initiation doses” would work better when patients are younger, healthier, and relatively free of acute illnesses, as is the case in many outpatient clinics. Of course, the one major drawback of more dramatic forms of loading doses is the fear of inducing the aforementioned necrotic skin reaction from an acute protein C deficiency. In reality, however, these necrotic reactions have been observed most commonly in patients who received much larger loading doses than 10 mg.
On the other hand, for the treatment of active thromboembolic events, the proper front-loading regimen may still have the potential to more consistently attain the desired target INR by the fourth or fifth day instead of a few days later. Given the average daily cost of enoxaparin of at least $15 to $20 per day for prophylaxis and $50 to $100 per day for treatment, a high-volume service or institution that could reduce its enoxaparin-warfarin overlap period, by even a day or two per case, might be able to markedly reduce its annual pharmaceutical costs.
Clinicians must consider a plethora of factors when administering warfarin. Despite the many reasonably successful studies that have used “nomograms” to initiate and manage warfarin therapy, questions remain as to how to best titrate the agent to obtain a therapeutic INR quickly and safely. Because of the possibility of increased bleeding and heightened drug sensitivity, the appropriate use of warfarin is especially challenging in the geriatric population. Indeed, both underdosing and overdosing may lead to increased morbidity and mortality, longer hospital stays, and increased health care costs. Of course, the intensity of anticoagulation and the duration of treatment should be tailored according to the indication of treatment and to the presence or absence of both acute and chronic illnesses.
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Doses should be initiated and adjustments should be made with an adequate understanding of warfarin’s mechanism of action, its pharmacokinetics, and its proclivities for drug-drug interactions. More research is needed to clarify which types of “front-loading” regimens, if any, can be used to foster the most rapid, consistent, and safe titration to a therapeutic INR. Clinicians who administer warfarin, when using any nomo-gram, should consider such mitigating factors as the patient’s age and nutritional status, the presence of an acute illness, and possible drug-drug interactions.