Warfarin in Antiphospholipid Syndrome — Time to Explore New Horizons

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 roughly 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 clinical 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 optimal 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-

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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 had received low-dose aspirin for sec- require frequent blood monitoring and dose adjustments, ondary thrombosis prevention. In this small cohort, recur- sometimes as often as 2–3 times per week, both an incon- rent stroke rate was 3.5 per 100 patient-years (2/8 patients). venience for the patient and a financial burden for the Both patients with recurrent events were smokers at the time healthcare system. Other potential reasons for frequent dose of the first and recurrent strokes39. In summary, unlike the adjustments include noncompliance, laboratory errors, recommendations from retrospective studies, aspirin is an hereditary warfarin resistance, and hypermetabolic condi- option for selected aPL-positive patients presenting with tions such as fever or hyperthyroidism. Despite frequent arterial events. dose adjustments, achieving the target INR range can be a Antiplatelet agents such as dipyridamole, aspirin with challenge. Several studies have shown that patients on dipyridamole (Aggrenox), ticlopidine (Ticlid), or clopido-

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Downloaded on October 2, 2021 from www.jrheum.org grel bisulfate (Plavix) have been used for secondary preven- in patients undergoing hip fracture surgery or total hip/knee tion after non-cardioembolic strokes or TIA. Dipyridamole replacement surgeries20. Fondaparinux is currently being inhibits platelet activation by blocking the uptake of adeno- evaluated for arterial thrombosis, and no data exist in aPL- sine, which results in reduced platelet cytosolic calcium, and positive patients. dipyridamole use combined with aspirin has additive Thrombin, which converts fibrinogen to fibrin, can be inhibitory effects on platelets40. Ticlopidine and clopidogrel inhibited indirectly (via antithrombin III) or directly (via inhibit ADP-induced binding of fibrinogen to platelets, binding to thrombin and inhibiting its interaction). The which is necessary for platelet aggregation and thrombin intravenous direct thrombin inhibitors lepirudin and arga- formation. troban have been approved for patients with heparin- In the American College of Chest Physicians treatment induced thrombocytopenia, and bivalirudin has been guidelines for the secondary prevention of stroke, aspirin is approved for patients with acute coronary syndrome under- recommended as the least expensive initial therapy. going percutaneous interventions20,45. Due to irreversible Clopidogrel, ticlopidine, and the combination of aspirin/ binding to thrombin, lepirudin can be associated with excess dipyridamole are other options41. There are no direct com- bleeding. No data on use of these agents in aPL-positive parison safety data on aspirin/dipyridamole or clopidogrel patients exist; however these agents have been given to with warfarin. In 2 prospective trials, the incidence of hem- patients with APS with heparin-induced thrombocytopenia. orrhagic complications did not differ significantly between Ximelagatran is the first oral thrombin inhibitor that neu- antiplatelet agents (aspirin/dipyridamole, clopidogrel) and tralizes clot-bound thrombin. The active metabolite of xime- aspirin42,43. lagatran is melagatran, which has a wider therapeutic win- Antiplatelet agents other than aspirin have been given dow than warfarin. Ximelagatran is superior to warfarin for empirically to some patients with APS, but they have never the prevention of venous thromboembolism after total knee been formally tested in clinical trials. In a recent retrospec- replacement surgery46. In a randomized, double blind study, tive study, we determined the clinical characteristics and ximelagatran was superior to placebo for the extended pre- outcomes of aPL-positive patients who have been treated vention (6–18 months after warfarin treatment) of venous with these agents for thrombosis prevention44. Four patients thromboembolism47. Ximelagatran caused transient liver with definite APS did not develop recurrent thrombosis function elevations, but levels decreased spontaneously while being treated with clopidogrel during a mean fol- whether the medication was continued or not; further stud- lowup of 27.3 months. Although this was a pilot study with ies are in progress. Ximelagatran has no known interaction a small number of patients, our data suggested that treatment with drugs or food. Ximelagatran is also being evaluated for with new antiplatelet agents may be an alternative to war- arterial thrombosis, and clearly has the potential to replace farin and may prevent subsequent aPL-related ischemic warfarin for certain patients. events. The anticoagulant protein C pathway is activated when Heparin and other heparin products act indirectly (via thrombin binds to thrombomodulin on the endothelial cell antithrombin) on thrombin and factor Xa. As with the new surface. Activated protein C inactivates factor Va and factor antiplatelet agents, no controlled studies exist on the VIIIa, which eventually decreases thrombin generation. longterm use of heparin for secondary thrombosis preven- Recombinant activated protein C has been approved for the tion in APS, although heparin has been used empirically in management of sepsis, where microvascular thrombosis is a warfarin-resistant patients with APS. As part of our pilot critical pathophysiological finding48. No data exist with study described above, we also analyzed 7 aPL-positive respect to activated protein C and APS; however, this agent patients treated with therapeutic dose low molecular weight can be considered in patients with catastrophic APS who heparin (LMWH) for secondary thrombosis prevention44. have significant small vessel involvement. Based on our observation in 4 patients, LMWH may not be Some other new anticoagulant drugs that are still in phase as effective as warfarin for the secondary prevention of II developmental stages include nematode anticoagulant thrombosis in APS, as 4 of 5 patients with definite APS had peptide (NAPc2), which inhibits factor VIIa within the fac- recurrent thrombotic events. tor VII-tissue factor complex by binding to a noncatalytic site on factor X or factor Xa; active-site blocked factor VIIa New Anticoagulants (FVIIai), which decreases the initiation of coagulation by Fondaparinux, a new subcutaneous synthetic pentasaccha- competing with factor VIIa for tissue factor binding; and ride, is the antithrombin binding unit of heparin that binds to idraparinux, DX-9065a, and DPC 906, which are direct fac- antithrombin III to indirectly inhibit factor Xa and eventual- tor Xa inhibitors20. ly thrombin generation. Fondaparinux is as effective as A recent review article by Roubey discussed other possi- heparin in the acute treatment of venous thromboem- ble approaches to the prevention of thrombosis in APS, bolism20, is administered once daily, does not require blood including statins, hydroxychloroquine, inhibition of mono- monitoring, and has been approved for thromboprophylaxis cyte tissue factor expression, and LJP 1082 (ß2-GPI-specif-

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Downloaded on October 2, 2021 from www.jrheum.org ic B cell toleragen)49. However, with our current knowledge 5. Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, and in the absence of controlled randomized trials, these Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med agents cannot be recommended alone for secondary throm- 1995;332:993-7. bosis prevention in APS. 6. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical In conclusion, despite the effectiveness of warfarin in course after the first thrombotic event in 70 patients. Ann Intern secondary thrombosis prevention in APS, warfarin use is Med 1992;117:303-8. cumbersome for both patients and physicians due to signifi- 7. Derksen RH, de Groot PG, Kater L, Nieuwenhuis HK. Patients with antiphospholipid antibodies and venous thrombosis should cant bleeding complications and the need for frequent blood receive long-term anticoagulant treatment. Ann Rheum Dis monitoring. 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Duration of Anticoagulation Study Group. therapy), and these agents can also be associated with iatro- Am J Med 1998;104:332-8. 10. Ginsberg JS, Wells PS, Brill-Edwards P, et al. Antiphospholipid genic bleeding complications. However, we believe that antibodies and venous thromboembolism. Blood 1995;86:3685-91. their effectiveness, cost, side effects including the risk of 11. Prandoni P, Simioni P, Girolami A. Antiphospholipid antibodies, bleeding, and need for monitoring will determine their place recurrent thromboembolism, and intensity of warfarin in our clinical armamentarium. It is highly likely that during anticoagulation [letter]. Thromb Haemost 1996;75:859. the next decade, warfarin and heparin will no longer be the 12. Rance A, Emmerich J, Fiessinger JN. Anticardiolipin antibodies and recurrent thromboembolism. Thromb Haemost 1997;77:221-2. first choice of anticoagulants for aPL-negative and positive 13. Elezovic I, Miljic P, Antunovic P, et al. 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