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Editorial
Warfarin in Antiphospholipid Syndrome — Time to Explore New Horizons
DORUK ERKAN, MD,
Department of Rheumatology, Hospital for Special Surgery, Weill Medical College of Cornell University, 535 East 70th Street, New York, New York 10021; THOMAS L. ORTEL, MD, PhD, Division of Hematology, Duke University Medical Center, Durham, North Carolina; MICHAEL D. LOCKSHIN, MD, Department of Rheumatology, Hospital for Special Surgery, Weill Medical College of Cornell University, New York, New York, USA Antiphospholipid syndrome (APS) constitutes vascular thrombosis and/or pregnancy morbidity occurring in persons with antiphospholipid antibodies (aPL), most commonly a positive lupus anticoagulant (LAC) test, anticardiolipin antibodies (aCL), and anti-ß2-glycoprotein I antibodies (ß2-GPI)1. Given the wide spectrum of aPL-related clinical manifestations and significant morbidity and mortality due to APS2, primary and secondary thrombosis prevention is crucial. Primary thrombosis prevention lacks an evidence-based approach; controlled, prospective, and randomized studies are in progress3,4. For secondary thrombosis prevention, the current recommendation is life-long warfarin; the necessity, duration, and intensity of warfarin treatment are still under debate. Further, warfarin use is cumbersome due to bleeding complications, frequent blood monitoring, and teratogenicity. In the longterm management of patients with APS, experience with warfarin alternatives (such as antiplatelet agents) is empirical and the need for new anticoagulant agents (such as direct and indirect thrombin inhibitors) is vital. Necessity and Duration of Warfarin Both retrospective and prospective studies have shown the efficacy of warfarin for secondary thrombosis prevention in APS5-14. Based on retrospective studies, 20–70% of patients with APS develop recurrent thrombosis when they stop anticoagulation5-8. Schulman, et al showed prospectively that aPL-positive patients have a higher risk of thrombosis recurrence compared to aPL-negative patients when they stop anticoagulation after 6 months (29% vs 14% over 4 years' followup)9. However, these studies did not address the optimal duration of therapy or when anticoagulation can be discontinued. Most importantly, these studies did not include an extensive evaluation of risk factors other than the presence of aPL. Other well established reversible risk factors for thrombosis can coexist in APS patients at the time of an event, and may even be responsible for triggering acute thrombosis15-18. In addition, the effectiveness of anticoagulation beyond 6 months is not unique to aPL-positive patients; Ridker, et al recently reported in a randomized, double blind, placebo controlled study that patients with idiopathic venous thromboembolism have significant reduction in the risk of recurrent venous thrombosis when they continue to receive warfarin with a target international normalized ratio (INR) of 1.5 to 2.019. The risk of venous thromboembolism is roughly 10% per year whether warfarin is stopped after 3, 6, 12, or 27 months in aPL-negative patients with unprovoked thrombosis20. Thus, no compelling data exist about the optimal duration of therapy or when anticoagulation can be discontinued in APS patients. Ideally, anticoagulation should be stopped when the risks of treatment outweigh the risks of thrombosis21. Currently it is not possible to predict which patients with APS will develop recurrent thrombosis when warfarin treatment is stopped, and there is no evidence for or against indefinite anticoagulation in patients with APS who develop events in the presence of other clinical thrombotic risk factors or a precipitating event. Hypothetically, if a patient develops a vascular event in the presence of other obvious hypercoagulable risk factors, that patient may be less likely to develop a recurrent event if the warfarin treatment is stopped when the trigger event is no longer persistent. Our definition of an APS patient at low risk of recurrent thrombosis after warfarin discontinuation includes a history of a single vascular thrombotic event; development of this event in the presence of a second thrombotic risk factor (oral contraceptive use or hormone replacement therapy, pregnancy, or perioperative period); and stable disease (no recurrent vascular events) for at least 2 years. We believe that risk-stratified controlled prospective studies are urgently needed for secondary thrombosis prevention in APS. Intensity of Warfarin Retrospective studies have shown that high-intensity anticoagulation (INR > 3.0) protects better against recurrence than low-intensity anticoagulation (INR 2.0–3.0) for secondary thrombosis prevention in APS5-7; however, these findings were not confirmed by prospective studies. Several prospective studies involving APS patients with only venous thrombosis conclude that low-intensity anticoagulation is adequate for longterm management9-12. A recent Canadian consortium, in the first prospective randomized controlled trial comparing 2 intensities of warfarin, concluded that both low and high-intensity anticoagulation are similarly effective for low-risk APS patients with either arterial or venous events22. As patients with arterial events made up only one-fifth of studied patients, the debate on the intensity of anticoagulation continues for APS patients with arterial events. However, this study now definitively permits less intense anticoagulation for selected APS patients with venous events23. Bleeding Complications On average, the risk of major bleeding in patients receiving warfarin is 3% per year, of which roughly 20% are fatal14,24,25. Even with a therapeutic INR, patients are still at risk for bleeding and with an INR of 2.0 to 3.0, annual rates of major, life threatening, and fatal bleeding rates are 2%, 1%, and 0.25%, respectively26. Every 1-point rise in INR increases the risk for major bleeding by 42%27 and high-intensity anticoagulation carries an increased risk of bleeding28; bleeding rates are higher for patients receiving high-intensity (INR 3.0–4.5) compared to low-intensity (2.0–2.5) warfarin (22.4% vs 4.3%; p = 0.015)29. In 3 studies, 5 of 55, 2 of 19, and 29 of 104 aPL-positive patients receiving warfarin developed severe hemorrhagic complications, respectively5-7. Although one recent retrospective study found no increased incidence of intracranial or fatal bleeding in patients with APS receiving high-intensity warfarin, the anticoagulation control was not strict; only 37% of INR results during the study were within the therapeutic range30. Concomitant hypertension, history of cerebrovascular accident, gastrointestinal bleeding and anticoagulation-related bleeding, use of other medications such as aspirin or nonsteroidal antiinflammatory drugs, older age, reliability of the patient, and drug interactions of warfarin with other medications contribute to the risk of bleeding. In addition to these risk factors, less than 1.5% of the population has a mutation in the factor IX propeptide that is associated with an enhanced response to warfarin therapy, significantly decreased factor IX levels, and bleeding even with a therapeutic INR31. Frequent Blood Monitoring Both diet (mainly vitamin K-containing products) and drug interactions (that directly affect warfarin's absorption and clearance) can alter INR32. Patients receiving warfarin require frequent blood monitoring and dose adjustments, sometimes as often as 2–3 times per week, both an inconvenience for the patient and a financial burden for the healthcare system. Other potential reasons for frequent dose adjustments include noncompliance, laboratory errors, hereditary warfarin resistance, and hypermetabolic conditions such as fever or hyperthyroidism. Despite frequent dose adjustments, achieving the target INR range can be a challenge. Several studies have shown that patients on longterm anticoagulation are out of therapeutic range in 35–60% of blood draws33. Teratogenicity Although 2 recent studies addressed the use of warfarin in pregnant patients with APS in the second and third trimesters and found no teratogenicity or significant maternal hemorrhage34,35, warfarin use during early pregnancy can be associated with a high incidence of fetal loss and congenital malformations36. Warfarin crosses the placenta and causes abnormalities in the fetus, especially when taken during the first trimester after the sixth week of gestation, and may also cause fatal hemorrhage in the fetus in utero. The current standard of care in the United States is to stop warfarin before conception. Warfarin Alternatives Aspirin blocks the cyclooxygenase enzyme and inhibits the synthesis of thromboxane A2, a potent stimulator of platelet aggregation and vasoconstriction. Aspirin is the standard of care after an ischemic stroke or a transient ischemic attack (TIA) for the prevention of recurrence in aPL-negative patients. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) showed that warfarin with a target INR of 1.4 to 2.8 is not superior to aspirin in the secondary prevention of ischemic cerebrovascular events37. Although most aPL-positive patients with ischemic strokes currently receive life-long warfarin (based on retrospective studies warfarin is more effective than aspirin5,6), a recent prospective study (Antiphospholipid Antibody in Stroke — APASS) found no difference in the risk of recurrent stroke over a 2-year followup period in aPL-positive patients with ischemic stroke who were randomized to receive either aspirin (325 mg daily) or warfarin (INR between 1.4 and 2.8). APASS concluded that for selected older patients with positive aPL at the time of the stroke who do not have either atrial fibrillation or high-grade stenosis, aspirin and warfarin therapies (at a target INR of roughly 2.2) are equivalent in both efficacy and major bleeding complications38. The generalizability of the results is limited, as in the APASS study high-intensity warfarin treatment (INR > 3) was not administered, the study group had an average age of 60, and the aPL determination was performed only once at study entry. However, Derksen, et al reported 8 patients with APS with ischemic strokes who had received low-dose aspirin for secondary thrombosis prevention. In this small cohort, recurrent stroke rate was 3.5 per 100 patient-years (2/8 patients). Both patients with recurrent events were smokers at the time of the first and recurrent strokes39. In summary, unlike the recommendations from retrospective studies, aspirin is an option for selected aPL-positive patients presenting with arterial events. Antiplatelet agents such as dipyridamole, aspirin with dipyridamole (Aggrenox), ticlopidine (Ticlid), or clopidogrel bisulfate (Plavix) have been used for secondary prevention after non-cardioembolic strokes or TIA. Dipyridamole inhibits platelet activation by blocking the uptake of adenosine, which results in reduced platelet cytosolic calcium, and dipyridamole use combined with aspirin has additive inhibitory effects on platelets40. Ticlopidine and clopidogrel inhibit ADP-induced binding of fibrinogen to platelets, which is necessary for platelet aggregation and thrombin formation. In the American College of Chest Physicians treatment guidelines for the secondary prevention of stroke, aspirin is recommended as the least expensive initial therapy. Clopidogrel, ticlopidine, and the combination of aspirin/ dipyridamole are other options41. There are no direct comparison safety data on aspirin/dipyridamole or clopidogrel with warfarin. In 2 prospective trials, the incidence of hemorrhagic complications did not differ significantly between antiplatelet agents (aspirin/dipyridamole, clopidogrel) and aspirin42,43. Antiplatelet agents other than aspirin have been given empirically to some patients with APS, but they have never been formally tested in clinical trials. In a recent retrospective study, we determined the clinical characteristics and outcomes of aPL-positive patients who have been treated with these agents for thrombosis prevention44. Four patients with definite APS did not develop recurrent thrombosis while being treated with clopidogrel during a mean followup of 27.3 months. Although this was a pilot study with a small number of patients, our data suggested that treatment with new antiplatelet agents may be an alternative to warfarin and may prevent subsequent aPL-related ischemic events. Heparin and other heparin products act indirectly (via antithrombin) on thrombin and factor Xa. As with the new antiplatelet agents, no controlled studies exist on the longterm use of heparin for secondary thrombosis prevention in APS, although heparin has been used empirically in warfarin-resistant patients with APS. As part of our pilot study described above, we also analyzed 7 aPL-positive patients treated with therapeutic dose low molecular weight heparin (LMWH) for secondary thrombosis prevention44. Based on our observation in 4 patients, LMWH may not be as effective as warfarin for the secondary prevention of thrombosis in APS, as 4 of 5 patients with definite APS had recurrent thrombotic events. New Anticoagulants Fondaparinux, a new subcutaneous synthetic pentasaccharide, is the antithrombin binding unit of heparin that binds to antithrombin III to indirectly inhibit factor Xa and eventually thrombin generation. Fondaparinux is as effective as heparin in the acute treatment of venous thromboembolism20, is administered once daily, does not require blood monitoring, and has been approved for thromboprophylaxis in patients undergoing hip fracture surgery or total hip/knee replacement surgeries20. Fondaparinux is currently being evaluated for arterial thrombosis, and no data exist in aPL-positive patients. Thrombin, which converts fibrinogen to fibrin, can be inhibited indirectly (via antithrombin III) or directly (via binding to thrombin and inhibiting its interaction). The intravenous direct thrombin inhibitors lepirudin and argatroban have been approved for patients with heparin-induced thrombocytopenia, and bivalirudin has been approved for patients with acute coronary syndrome undergoing percutaneous interventions20,45. Due to irreversible binding to thrombin, lepirudin can be associated with excess bleeding. No data on use of these agents in aPL-positive patients exist; however these agents have been given to patients with APS with heparin-induced thrombocytopenia. Ximelagatran is the first oral thrombin inhibitor that neutralizes clot-bound thrombin. The active metabolite of ximelagatran is melagatran, which has a wider therapeutic window than warfarin. Ximelagatran is superior to warfarin for the prevention of venous thromboembolism after total knee replacement surgery46. In a randomized, double blind study, ximelagatran was superior to placebo for the extended prevention (6–18 months after warfarin treatment) of venous thromboembolism47. Ximelagatran caused transient liver function elevations, but levels decreased spontaneously whether the medication was continued or not; further studies are in progress.Ximelagatran has no known interaction with drugs or food. Ximelagatran is also being evaluated for arterial thrombosis, and clearly has the potential to replace warfarin for certain patients. The anticoagulant protein C pathway is activated when thrombin binds to thrombomodulin on the endothelial cell surface. Activated protein C inactivates factor Va and factor VIIIa, which eventually decreases thrombin generation. Recombinant activated protein C has been approved for the management of sepsis, where microvascular thrombosis is a critical pathophysiological finding48. No data exist with respect to activated protein C and APS; however, this agent can be considered in patients with catastrophic APS who have significant small vessel involvement. Some other new anticoagulant drugs that are still in phase II developmental stages include nematode anticoagulant peptide (NAPc2), which inhibits factor VIIa within the factor VII-tissue factor complex by binding to a noncatalytic site on factor X or factor Xa; active-site blocked factor VIIa (FVIIai), which decreases the initiation of coagulation by competing with factor VIIa for tissue factor binding; and idraparinux, DX-9065a, and DPC 906, which are direct factor Xa inhibitors20. A recent review article by Roubey discussed other possible approaches to the prevention of thrombosis in APS, including statins, hydroxychloroquine, inhibition of monocyte tissue factor expression, and LJP 1082 (ß2-GPI-specific B cell toleragen)49. However, with our current knowledge and in the absence of controlled randomized trials, these agents cannot be recommended alone for secondary thrombosis prevention in APS. In conclusion, despite the effectiveness of warfarin in secondary thrombosis prevention in APS, warfarin use is cumbersome for both patients and physicians due to significant bleeding complications and the need for frequent blood monitoring. Further, the optimal management of patients with APS still lacks an evidence-based approach; as the variables of longterm anticoagulation are unknown, patients with APS receive life-long warfarin. Alternative safer agents should be tested in risk-stratified clinical trials. Several new anticoagulant agents are in various developmental stages. The use of new agents will not completely resolve the controversies of APS management (such as the duration of the therapy), and these agents can also be associated with iatrogenic bleeding complications. However, we believe that their effectiveness, cost, side effects including the risk of bleeding, and need for monitoring will determine their place in our clinical armamentarium. 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Is there a role for non-warfarin agents in the long-term management of antiphospholipid syndrome? [abstract]. Arthritis Rheum 2003;48 Suppl:S357. 45. Hyers TM. Management of venous thromboembolism: past, present, and future. Arch Intern Med 2003;163:759-68. [MEDLINE] 46. Francis CW, Berkowitz SD, Comp PC, et al. Ximelagatran for prevention of venous thromboembolism in knee replacement. J Arthroplasty 2004;19:258. 47. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H, THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-21. [MEDLINE] 48. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis. JAMA 2003;290:238-47. [MEDLINE] 49. Roubey RA. New approaches to prevention of thrombosis in the antiphospholipid syndrome: hopes, trials, and tribulations. Arthritis Rheum 2003;48:3004-8. [MEDLINE] |
