Moderate vs. High-Intensity Warfarin for Prevention of Recurrent Thrombosis - Moderate vs. High-Intensity Warfarin for Prevention of Recurrent Thrombosis

Nov 10, 2003
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Date Published:
01/01/2003
Date Updated:
11/10/2003
Original Posted Date:
11/10/2003
References

Description:

The goal of the trial was to evaluate treatment with high-intensity warfarin compared with moderate-intensity warfarin in preventing thrombosis in patients with antiphospholipid antibodies and previous thrombosis.

Hypothesis:

High-intensity warfarin is more effective in preventing thrombosis than moderate-intensity warfarin in patients with antiphospholipid antibodies and previous thrombosis.

Study Design

Study Design:

Patients Screened: 325
Patients Enrolled: 114
Mean Follow Up: mean 2.7 years
Mean Patient Age: mean age 42 years
Female: 60%

Patient Populations:

Objectively confirmed arterial or venous thrombosis and a positive test for antiphospholipid antibodies on two occasions at least three months apart. Criteria included presence of lupus anticoagulant, a moderate or high titer of immunoglobulin G (IgG) anticardiolipin antibody, or both.

Exclusions:

Only IgM anticardiolipin antibodies; clinically significant bleeding diathesis; history of intracranial hemorrhage, stroke, or gastrointestinal bleeding within the previous three months; a contraindication to warfarin; history of objectively confirmed recurrent thrombosis while receiving warfarin targeted to an INR of ≥2.0; pregnancy or a planned pregnancy during the study period; or a geographic location that would preclude follow-up

Primary Endpoints:

Efficacy: recurrent thrombosis, defined as a stroke or transient ischemic attack, MI, peripheral arterial thrombosis, cerebral-vein thrombosis, deep-vein thrombosis, or pulmonary embolism, confirmed by adjudication.

Safety: bleeding.

Drug/Procedures Used:

Patients were randomized in a double-blind manner to moderate-intensity warfarin (international normalized ratio [INR] 2.0-3.0; n=58) or high-intensity warfarin (INR 3.1-4.0; n=56). INR results were forwarded to central warfarin monitors in order to maintain blinding.

Principal Findings:

Mean INR values were 2.3 in the moderate-intensity group and 3.3 in the high-intensity group. The proportion of female patients was significantly higher in the moderate-intensity warfarin arm (71% vs. 48%, p=0.01). Other baseline characteristics were similar in the two arms.

There was no difference in the primary endpoint of recurrent thrombosis between the treatment arms: 10.7% (6/56) in the high-intensity group and 3.4% (2/58) in the moderate-intensity group (hazard ratio [HR] for the high-intensity group, 3.1, 95% confidence interval [CI] 0.6-15.0, p=0.15). The recurrence in the moderate-intensity arm was a myocardial infarction [MI] in a patient with a prior MI (INR 1.6) and a deep-vein thrombosis in a patient with prior deep-vein thrombosis (INR 2.8). No patients died during the study.

Major bleeding occurred in three patients in the high-intensity warfarin group and in four patients in the moderate-intensity group (HR 1.0, 95% CI 0.2-4.8, p=0.96). There was no difference in episodes of any bleeding between arms (25%, 14/56 with high-intensity vs. 19%, 11/58 with moderate intensity, HR 1.9, 95% CI 0.8-4.2, p=0.13).

Interpretation:

Among patients with antiphospholipid antibodies and previous thrombosis, treatment with high-intensity warfarin therapy was not associated with a difference in the primary endpoint of recurrent thrombosis compared with moderate-intensity warfarin therapy. Prior studies had suggested an association between a higher risk of recurrent thrombosis with moderate-intensity warfarin therapy in patients with antiphospholipid antibody syndrome. However, the studies were retrospective and nonrandomized.

The present trial was the first randomized, double-blind study to evaluate these therapies. Data from the present trial do not address the effectiveness of the warfarin dose in the first three months after the initial episode of thrombosis because the inclusion criteria required two antiphospholipid-antibody tests three months apart.

References:

Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003;349:1133-8.

Keywords: Immunoglobulin G, Myocardial Infarction, Warfarin, Antibodies, Anticardiolipin, Antibodies, Antiphospholipid, International Normalized Ratio, Antiphospholipid Syndrome, Lupus Coagulation Inhibitor, Thrombosis, Venous Thrombosis, Confidence Intervals, Hemorrhage


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