Editorial Warfarin in Antiphospholipid Syndrome — Time to Explore New Horizons Antiphospholipid syndrome (APS) constitutes vascular boembolism have significant reduction in the risk of recur- thrombosis and/or pregnancy morbidity occurring in per- rent venous thrombosis when they continue to receive war- sons with antiphospholipid antibodies (aPL), most com- farin with a target international normalized ratio (INR) of monly a positive lupus anticoagulant (LAC) test, anticardi- 1.5 to 2.019. The risk of venous thromboembolism is rough- ly 10% per year whether warfarin is stopped after 3, 6, 12, olipin antibodies (aCL), and anti-ß2-glycoprotein I antibod- 1 or 27 months in aPL-negative patients with unprovoked ies (ß2-GPI) . Given the wide spectrum of aPL-related clin- ical manifestations and significant morbidity and mortality thrombosis20. due to APS2, primary and secondary thrombosis prevention Thus, no compelling data exist about the optimal dura- is crucial. Primary thrombosis prevention lacks an evidence- tion of therapy or when anticoagulation can be discontinued based approach; controlled, prospective, and randomized in APS patients. Ideally, anticoagulation should be stopped studies are in progress3,4. For secondary thrombosis preven- when the risks of treatment outweigh the risks of thrombo- tion, the current recommendation is life-long warfarin; the sis21. Currently it is not possible to predict which patients necessity, duration, and intensity of warfarin treatment are with APS will develop recurrent thrombosis when warfarin still under debate. Further, warfarin use is cumbersome due treatment is stopped, and there is no evidence for or against to bleeding complications, frequent blood monitoring, and indefinite anticoagulation in patients with APS who devel- teratogenicity. In the longterm management of patients with op events in the presence of other clinical thrombotic risk APS, experience with warfarin alternatives (such as factors or a precipitating event. Hypothetically, if a patient antiplatelet agents) is empirical and the need for new anti- develops a vascular event in the presence of other obvious coagulant agents (such as direct and indirect thrombin hypercoagulable risk factors, that patient may be less likely inhibitors) is vital. to develop a recurrent event if the warfarin treatment is stopped when the trigger event is no longer persistent. Our Necessity and Duration of Warfarin definition of an APS patient at low risk of recurrent throm- Both retrospective and prospective studies have shown the bosis after warfarin discontinuation includes a history of a efficacy of warfarin for secondary thrombosis prevention in single vascular thrombotic event; development of this event APS5-14. Based on retrospective studies, 20–70% of patients in the presence of a second thrombotic risk factor (oral con- with APS develop recurrent thrombosis when they stop anti- traceptive use or hormone replacement therapy, pregnancy, coagulation5-8. Schulman, et al showed prospectively that or perioperative period); and stable disease (no recurrent aPL-positive patients have a higher risk of thrombosis recur- vascular events) for at least 2 years. We believe that risk- rence compared to aPL-negative patients when they stop stratified controlled prospective studies are urgently needed anticoagulation after 6 months (29% vs 14% over 4 years’ for secondary thrombosis prevention in APS. followup)9. However, these studies did not address the opti- mal duration of therapy or when anticoagulation can be dis- Intensity of Warfarin continued. Most importantly, these studies did not include Retrospective studies have shown that high-intensity anti- an extensive evaluation of risk factors other than the pres- coagulation (INR > 3.0) protects better against recurrence ence of aPL. Other well established reversible risk factors than low-intensity anticoagulation (INR 2.0–3.0) for sec- for thrombosis can coexist in APS patients at the time of an ondary thrombosis prevention in APS5-7; however, these event, and may even be responsible for triggering acute findings were not confirmed by prospective studies. Several thrombosis15-18. prospective studies involving APS patients with only In addition, the effectiveness of anticoagulation beyond 6 venous thrombosis conclude that low-intensity anticoagula- months is not unique to aPL-positive patients; Ridker, et al tion is adequate for longterm management9-12. A recent recently reported in a randomized, double blind, placebo Canadian consortium, in the first prospective randomized controlled study that patients with idiopathic venous throm- controlled trial comparing 2 intensities of warfarin, con- Personal non-commercial use only. The Journal of Rheumatology Copyright © 2005. All rights reserved. 208 The Journal of Rheumatology 2005; 32:2 Downloaded on October 2, 2021 from www.jrheum.org cluded that both low and high-intensity anticoagulation are longterm anticoagulation are out of therapeutic range in similarly effective for low-risk APS patients with either 35–60% of blood draws33. arterial or venous events22. As patients with arterial events made up only one-fifth of studied patients, the debate on the Teratogenicity intensity of anticoagulation continues for APS patients with Although 2 recent studies addressed the use of warfarin in arterial events. However, this study now definitively permits pregnant patients with APS in the second and third less intense anticoagulation for selected APS patients with trimesters and found no teratogenicity or significant mater- venous events23. nal hemorrhage34,35, warfarin use during early pregnancy can be associated with a high incidence of fetal loss and con- Bleeding Complications genital malformations36. Warfarin crosses the placenta and On average, the risk of major bleeding in patients receiving causes abnormalities in the fetus, especially when taken dur- warfarin is 3% per year, of which roughly 20% are ing the first trimester after the sixth week of gestation, and fatal14,24,25. Even with a therapeutic INR, patients are still at may also cause fatal hemorrhage in the fetus in utero. The risk for bleeding and with an INR of 2.0 to 3.0, annual rates current standard of care in the United States is to stop war- of major, life threatening, and fatal bleeding rates are 2%, farin before conception. 1%, and 0.25%, respectively26. Every 1-point rise in INR increases the risk for major bleeding by 42%27 and high- Warfarin Alternatives intensity anticoagulation carries an increased risk of bleed- Aspirin blocks the cyclooxygenase enzyme and inhibits the 28 ing ; bleeding rates are higher for patients receiving high- synthesis of thromboxane A2, a potent stimulator of platelet intensity (INR 3.0–4.5) compared to low-intensity (2.0–2.5) aggregation and vasoconstriction. Aspirin is the standard of warfarin (22.4% vs 4.3%; p = 0.015)29. In 3 studies, 5 of care after an ischemic stroke or a transient ischemic attack 55, 2 of 19, and 29 of 104 aPL-positive patients receiving (TIA) for the prevention of recurrence in aPL-negative warfarin developed severe hemorrhagic complications, patients. The Stroke Prevention in Reversible Ischemia Trial respectively5-7. Although one recent retrospective study (SPIRIT) showed that warfarin with a target INR of 1.4 to found no increased incidence of intracranial or fatal bleed- 2.8 is not superior to aspirin in the secondary prevention of ing in patients with APS receiving high-intensity warfarin, ischemic cerebrovascular events37. Although most aPL-pos- the anticoagulation control was not strict; only 37% of INR itive patients with ischemic strokes currently receive life- results during the study were within the therapeutic long warfarin (based on retrospective studies warfarin is range30. more effective than aspirin5,6), a recent prospective study Concomitant hypertension, history of cerebrovascular (Antiphospholipid Antibody in Stroke — APASS) found no accident, gastrointestinal bleeding and anticoagulation- difference in the risk of recurrent stroke over a 2-year fol- related bleeding, use of other medications such as aspirin or lowup period in aPL-positive patients with ischemic stroke nonsteroidal antiinflammatory drugs, older age, reliability who were randomized to receive either aspirin (325 mg of the patient, and drug interactions of warfarin with other daily) or warfarin (INR between 1.4 and 2.8). APASS con- medications contribute to the risk of bleeding. In addition to cluded that for selected older patients with positive aPL at these risk factors, less than 1.5% of the population has a the time of the stroke who do not have either atrial fibrilla- mutation in the factor IX propeptide that is associated with tion or high-grade stenosis, aspirin and warfarin therapies an enhanced response to warfarin therapy, significantly (at a target INR of roughly 2.2) are equivalent in both effi- decreased factor IX levels, and bleeding even with a thera- cacy and major bleeding complications38. The generaliz- peutic INR31. ability of the results is limited, as in the APASS study high- intensity warfarin treatment (INR > 3) was not adminis- Frequent Blood Monitoring tered, the study group had an average age of 60, and the aPL Both diet (mainly vitamin K-containing products) and drug determination was performed only once at study entry. interactions (that directly affect warfarin’s absorption and However, Derksen, et al reported 8 patients with APS with clearance) can alter INR32. Patients receiving warfarin ischemic strokes who