Abstracts & Commentary
Synopsis: The study found that high-intensity warfarin therapy was not necessary for the prevention of recurrent thrombosis in the APA syndrome.
Sources: Crowther MA, et al. N Eng J Med. 2003;349:1133-1138; Lockshin MD, Erkan D. Editorial. N Eng J Med. 2003;349:1177-1179.
The antiphospholipid antibody (APA) syndrome comprises a wide range of clinical features, including thromboembolism, fetal loss, thrombocytopenia, livido reticularis, cardiac valve vegetations, a multiple sclerosis-like condition, and progressive cognitive dysfunction—all associated with the persistence of moderate-to-high levels of IgG or IgM anticardiolipin antibodies or the lupus anticoagulant.
The varied clinical presentation of APA syndrome has led to various types of treatment. In pregnant women with a history of recurrent fetal loss, low doses of unfractionated heparin have been effective in preventing fetal loss1 and thrombosis.2 In patients with the rare catastrophic APA syndrome of progressive multisystemic vascular occlusions plasmapheresis,3 intravenous immune globulin or both have been recommended. A retrospective study4 concluded that anticoagulant therapy at an international normalized ration (INR) of 3.0 or higher afforded better protection against recurrent thrombosis than less-intensive anticoagulation.
Crowther and associates reported the results of a prospective, randomized, controlled study of the use of 2 intensities of warfarin anticoagulation for prevention of thrombosis in patients with the APA syndrome who had previous thrombosis (see Table).
A total of 114 patients with moderate or high titers of anticardiolipin antibodies (n = 44), the lupus anticoagulant alone (n = 49), or both (n = 21) were treated with either moderate- or high-intensity warfarin anticoagulation. The follow-up period was 2.7 years. In both treatment groups, the rate of recurrent thrombosis was low: 2 of 58 patients (3.4%) assigned to receive moderate-intensity warfarin and 6 of 56 patients (10.7%) assigned to receive high-intensity warfarin. Therefore, the lower dose of warfarin was as effective as the higher dose. Adverse effects were similar among patients in the 2 groups.
As pointed out by Lockshin and Erkan in their editorial, adherence to protocol was imperfect. In the moderate-intensity group, the INR was above the target range 11% of the time, within range 71% of the time, and below it 19% of the time. In the high-intensity group, INR was above the range 17% of the time, within the range only 40% of the time, and below it 43% of the time. In 5 of 8 patients with recurrent thrombosis during the follow-up period, INR was lower than 2.0. Therefore, at the time of recurrent thrombosis, INR was out of range or subtherapeutic in 4 of the patients in the high-intensity warfarin group.
In addition, patients with arterial thrombosis, which in general is harder to treat than venous thrombosis, accounted for only one-fifth of the patients studied, although their outcomes were similar to those with venous thrombosis.
Comment by John J. Caronna, MD
The treatment of the APA syndrome has been empirical because of both the lack of well-designed prospective studies and the heterogeneity of the clinical syndromes. This heterogeneity derives in part from the fact that there are 2 APA syndromes: the primary APA syndrome not associated with another illness and the secondary APA syndrome associated with systemic lupus erythematosus or other rheumatic disease.
In addition, even the term "antiphospholipid antibody" is inaccurate. As Lockshin and Erkan point out, the most important autoantigens in the syndrome are not negatively charged phospholipids as originally thought. The principal autoantigen is ß2-glycoprotein I (apolipoprotein H) that binds cardiolipin and other phospholipids. The phospholipid that is bound by the glycoprotein probably induces a conformational charge in the protein, thereby causing it to expose an antigenic epitope.
The study of Crowther et al found that high-intensity warfarin therapy was not necessary for the prevention of recurrent thrombosis in the APA syndrome. It can be argued, however, that the rate of recurrent thrombosis might have been lower if the INR in patients assigned to high-intensity anticoagulation had been in the target range during a greater portion of the study period. Nevertheless, the rate of recurrent thrombosis in the moderate-intensity group was so low that it is unlikely that strict maintenance of an INR > 3 would have improved outcome.
Although the present study leaves many questions unanswered, such as the role of aspirin alone or in combination with warfarin in preventing thrombosis in the APA syndrome, the results appear to be valid and generalizable to the care of patients.
Dr. Caronna is Vice Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital, New York, NY.
1. Kutteh WH, Ermel LD. Am J Reprod Immunol. 1996;35:402-407.
2. Erkan D, et al. Arthritis Rheum. 2001;44:1466-1467.
3. Asherson RA, et al. Lupus. 2003;12:530-534.
4. Khamashta MA, et al. N Engl J Med. 1995;332: 993-997.