Moderate dose oral anticoagulant therapy in patients with the antiphospholipid syndrome? Yes


Mary-Frances Scully, Faculty of Medicine, Health Sciences Centre, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
Tel.: +1 709 777 4519/+1 709 777 8066; fax: +1 709 777 4292/+1 709 777 8060; e-mail:

Patients with the antiphospholipid syndrome have a higher risk of recurrent thrombosis after a first episode than do patients without the antiphospholipid syndrome and require long-term anticoagulation [1]. Retrospective studies reported that only high intensity oral anticoagulation is effective in preventing thrombotic recurrences [2–4]. Hence, many patients with the antiphospholipid syndrome and a history of venous or arterial thrombosis receive high intensity oral vitamin K anticoagulant therapy. Some also receive aspirin. There is an increasing evidence that high intensity warfarin carries a high risk of hemorrhagic complications and even death [5,6]. Hence, there was a gap in knowledge and a need for a prospective clinical trial comparing different dose intensities of warfarin in the management of patients with the antiphospholipid syndrome for the secondary prevention of thrombotic events. To address this gap, a Canadian group, led by Mark Crowther, planned a randomized double-blind trial comparing moderate intensity warfarin; INR 2.0–3.0, to high intensity warfarin; INR 3.1–4.0.

Management of patients with the antiphospholipid syndrome: is high intensity warfarin still the optimal therapy?

The objective of the Canadian group was to show that high intensity warfarin was more effective in preventing thrombosis than moderate intensity warfarin. Out of 325 patients screened in 13 participating centers, 207 met the inclusion criteria for the study. A total of 114 patients were enrolled in the study and followed for a mean of 2.7 years in the moderate intensity group and 2.6 years in the high intensity group. Recurrent thrombosis occurred in six of 56 (10.7%) patients, of those assigned to receive high intensity warfarin and in two of 58 (3.4%) patients of those assigned to receive moderate intensity warfarin. Major bleeding occurred in three patients assigned to receive high intensity warfarin and in four patients assigned to receive moderate intensity warfarin. This group concluded that high intensity warfarin was not superior to moderate intensity warfarin for thromboprophylaxis in patients with antiphospholipid antibodies. As the number of events was small, the confidence intervals appeared wide. In five out of eight patients who experienced a failure of thromboprophylaxis, one was off therapy and three other patients had subtherapeutic INR's of 1.6, 1.0, 0.9. One had a borderline level of 1.9 [7]. For some, this study demonstrated the well-known problem of maintaining intensity of oral anticoagulants rather than conclusively proving that moderate intensity anticoagulation is effective in this patient population. The most recent Chest guidelines recommend against high intensity warfarin (Grade 1A) [8].


Given the immense difficulty of recruiting patients with rare, complex disorders into prospective trials and following them for an adequate period of time, it is very fortuitous that Dr. Finazzi et al. had independently and concurrently planned a very similar randomized trial addressing the same issue which is published in the current issue of this journal. Patients in 26 centers in Europe and South America were screened and recruited for a perspective registry of patients with lupus anticoagulant. Out of 462 patients, 316 (68%) had a confirmed history of major arterial or venous thrombosis. After further screening, 109 patients with clinically confirmed antiphospholipid syndrome within the previous 5 years were enrolled in a prospective, randomized open-blinded endpoint adjudications designed study [9].

As in the Canadian study, patients were excluded from randomization, if they were less than 18 years of age (n = 8) or had a history of recurrent thrombosis during anticoagulation prophylaxis (n = 57), active bleeding or hemorrhagic disorders (n = 25), pregnancy, other comorbid conditions contraindicating oral anticoagulants or any serious illness with a life expectancy less than 3 years (n = 28). Inability to give informed consent or attend regular follow-up visits (n = 97). Another 31 patients were excluded from the trial for unknown reasons.

Further evidence from a second prospective randomized trial

In total, in the Finazzi study, 54 patients were assigned to receive high dose intensity warfarin and were compared with 52 patients who received moderate intensity warfarin and three patients who received 100 mg of aspirin daily. The mean follow-up was 3.2 years in the high intensity warfarin group and 2.5 years for patients receiving conventional warfarin. Recurrent thrombosis was observed in six of 54 patients (11.1%) assigned to receive high intensity warfarin and three of 55 (5.5%) assigned to receive conventional treatment. Major and minor bleeding occurred in 15 patients (27.8%) receiving high intensity warfarin (two major) and eight (14.6%) assigned to receive conventional treatment (three major).

The demographic and clinical characteristics of the patients enrolled in both randomized studies were comparable. Forty-seven percent of patients were age 40 years or less with a previous history of thrombotic events. Fifty percent had been diagnosed with the antiphospholipid syndrome in the year prior to recruitment in the study. Almost 70% of the patients enrolled in both studies were diagnosed with venous thromboembolism. Hence, these combined studies strongly suggest that for patients diagnosed with the antiphospholipid syndrome and venous thromboembolic events, it is reasonable to aim for a moderate intensity warfarin therapy of approximately 2.5 or 2–3. It is also important to note that another prospective randomized clinical trial studied a different subpopulation, of patients with the antiphospholipid syndrome (‘The antiphospholipid antibodies and subsequent thrombocclusive events in patients with ischemic stroke’ or APASS). Investigators failed to show that the presence of antiphospholipid, either lupus anticoagulant or anticardiolipin antibodies among patients with ischemic stroke predicted for increased risk of subsequent vascular occlusive events over 2 years nor a different response to aspirin vs. warfarin.

The ongoing dilemma of managing rare complex disorders in an ‘evidence-based’ world

Dr. Finnazi et al. with Dr. Crowther et al. are all to be congratulated and thanked for their efforts to produce evidence-based guidelines for the management of the antiphospholipid syndrome. Many problems remain. Both of these prospective randomized trials excluded patients with a high risk of bleeding and patients who had already recurred on moderate intensity anticoagulation. The studies do show conclusively that the current best evidence-based recommendation for secondary prevention for venous thromboembolism in patients with the antiphospholipid syndrome is long-term moderate intensity anticoagulation with an INR targeted at 2.5, (range 2.0–3.0). The optimal management of patients with a combination of the antiphospholipid syndrome and arterial events, patients at high risk of bleeding, those who fail standard prophylaxis and those who present with thrombi in unusual vascular beds is still unclear.

Perhaps, we now need to debate how to develop the infrastructure to support sufficient screening and recruitment of patients with rare thromboembolic disease and their long-term follow-up.