Эффективность и переносимость селективных и неселективных ингибиторов Ха-фактора при антифосфолипидном синдроме и системной красной волчанке: уровень анти-Ха-активности
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Seredavkina N.V., Reshetnyak T.M., Satybaldyeva M.A., et al. Effectiveness and safety of selective and non-selective factor Xa inhibitors in antiphospholipid syndrome and systemic lupus erythematosus: anti-Xa-activity range. Therapeutic Archive. 2019; 91 (5): 19–25. DOI: 10.26442/00403660.2019.05.000235
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Материалы и методы. У больных СКВ и АФС, длительно получавших низкомолекулярные гепарины (НМГ) и селективные ингибиторы Ха фондапаринукс и ривароксабан, ретроспективно проанализированы данные клинических и лабораторных исследований. В исследование включено 70 пациентов в возрасте 39 [31; 43] лет, из них 15/70 (21%) пациентов с СКВ, 10/70 (14%) – с АФС и 45/70 (65%) – с СКВ+АФС. Больные получали антикоагулянты: 29 пациентов – надропарин (98,3 [67,8; 129,5] МЕ/кг/сут), 29 пациентов – фондапаринукс (5 [5; 7,5] мг/сут), 3 больных – эноксапарин (1,2 [0,8; 1,5] мг/сут) и 9 пациентов – ривароксабан (20 мг/сут). Все пациенты подписали информированное согласие.
Результаты. Терапевтический интервал аХа 0,1–1,5 МЕ/мл зарегистрирован у 43/70 (61%) больных. Низкая аХа выявлена у 14/70 (20%) больных, высокая аХа – у 13/70 (19%). Пациентам с низкой аХа проводилась коррекция дозы антикоагулянта. Массивных кровотечений и рецидивов тромбозов в исследовании не зарегистрировано. Превышение терапевтического интервала аХа более часто встречалось на фоне фондапаринукса (31%), чем на фоне надропарина (7%) и ривароксабана (23%), р=0,02. На фоне эноксапарина аХа была в пределах нормы. В отсутствие кровотечения у больных СКВ и АФС, получавших антикоагулянты в стандартной терапевтической дозе, на повышение аХа оказывали влияние следующие факторы: порок сердца с формированием митральной недостаточности Ⅲ степени в исходе асептического эндокардита Либмана–Сакса (отношение шансов – ОШ 9,02, 95% доверительный интервал – ДИ [1,53; 53,12], p=0,015), поражение артерий по типу облитерирующего эндартериита (ОЭ) с артериальной недостаточностью (ОШ 6,86, 95% ДИ [1,25; 37,71], p=0,027), а также позитивность по всем трем серологическим маркерам АФС (ОШ 4,93, 95% ДИ [1,11; 21,99], p=0,036). Согласно полученной логистической регрессионной модели риск повышения аХа можно спрогнозировать по следующей формуле: Z = –3,98 + 2,2 × Порок (да–1/нет–0) + 1,9 × ОЭ (да–1/нет–0) + 1,6 × Triple-позитивность (да–1/нет–0). Значение классификационной функции Z=0,39 определяет группу пациентов с повышенным аХа. Соответственно значение Z>0,39 указывает на повышение аХа в отсутствие кровотечения, при этом чувствительность составляет 77%, специфичность – 86%, положительная прогностическая точность – 84,3%.
Заключение. На повышение аХа у больных АФС и СКВ влияли следующие клинические и иммунологические проявления: поражение сосудов по типу ОЭ, перенесенный асептический эндокардит Либмана–Сакса с формированием высокой степени митральной недостаточности, наличие всех трех маркеров АФС, что не требует коррекции дозы НМГ и фондапаринукса. Напротив, уменьшение дозы антикоагулянта может вызвать ухудшение клинической симптоматики. Терапевтическое окно аХа у таких пациентов должно быть расширено.
Ключевые слова: анти-Ха-активность, низкомолекулярные гепарины, фондапаринукс, системная красная волчанка, антифосфолипидный синдром.
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The aim of the study was to evaluate the anti-Xa-activity (aXa) of selective and non-selective factor Xa inhibitors in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) patients according to clinical implications and laboratory parameters.
Materials and methods. Clinical and laboratory data were analyzed retrospectively in SLE and APS patients who protractedly received low weight molecular heparins (LWMH) and selective factor Xa inhibitors fondaparinux and rivaroxaban. The study included 70 patients in the middle age 39 [31; 43] years: 15/70 (21%) – with SLE, 10/70 (14%) – with APS and 45/70 (65%) – with SLE and APS (SLE+APS). All the patients received anticoagulants: 29 patients – nadroparin (98.3 [67.8; 129.5] IU/kg/day), 29 patients – fondaparinux (5 [5; 7.5] mg/day), 3 patients – enoxaparin (1.2 [0.8; 1.5] mg/day) and 9 patients – rivaroxaban (20 mg/day). All the patients signed informed consents.
Results. aXa therapeutic range of 0.1–1.5 IU/ml was found in 43/70 (61%) patients, low aXa – in 14/70 (20%) and high aXa – in 13/70 (19%) patients. Patients with low aXa underwent anticoagulant dose correction. There were not any major bleedings and thrombosis relapses in the study. Increased aXa was more common in patients, who took fondaparinux (31%), than in those, who took nadroparin (7%) and rivaroxaban (23%), p=0.02. Patients with enoxaparin had normal aXa range. In the absence of bleeding in SLE and APS patients, received anticoagulants in standardized therapeutic dose, the next factors influenced the aXa range excess: valvular heart disease (VHD) with the 3rd stage of mitral valve insufficiency as a result of aseptic Libman–Sacks endocarditis (odds ratio – OR 9.02, 95% confidential interval – CI [1.53; 53.12], p=0.015), peripheral artery disease in analogy with arteritis obliterans (AO) (OR 6.86, 95% CI [1.25; 37.71], p=0.027), and also triple-positivity of all types of antiphospholipid antibodies (OR 4.93, 95% CI [1.11; 21.99], p=0.036). According to found logistic regression model, aXa range excess risk can be prognosticated by the next formula: Z = –3.98 + 2.2 × VHD (yes–1/no–0) + 1.9 × AO (yes–1/no–0) + 1.6 × Triple-positivity (yes–1/no–0). Classified function value Z=0.39 defines the patients group with aXa range excess. Thus the value Z>0.39 indicates aXa range excess in the absence of bleeding, herewith sensibility is of 77% and specificity is 86%, positive prognostic value is 84.3%.
Conclusion. In SLE and APS patients the next clinical and immunologic manifestations influenced the aXa therapeutic range excess: peripheral artery disease in analogy with AO, earlier aseptic Libman–Sacks endocarditis with the 3rd stage of mitral valve insufficiency and triple-positivity of all types of antiphospholipid antibodies, that does not need LWMH and fondaparinux dose correction. In contrast, anticoagulant dose reduction can cause clinical symptoms progression. Therapeutic aXa range in such patients should be extended.
Keywords: anti-Xa-activity, low weight molecular heparins, systemic lupus erythematosus, antiphospholipid syndrome.
2. Кириенко А.И., Панченко Е.П., Андрияшкин В.В. Венозный тромбоз в практике терапевта и хирурга. М.: Планида, 2012 [Kirienko AP, Panchenko EP, Andriyashkin VV. Venozny tromboz v praktike terapevta i hirurga. Moscow: Planida, 2012 (In Russ.)].
3. Streiff MB, Agnelli G, Connors JM, Crowther M, Eichinger S, Lopes R, McBane RD, Moll S, Ansell J. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis. 2016;41(1):32-67. https://doi.org/10.1007/s11239-015-1317-0
4. Решетняк Т.М. Лечение антифосфолипидного синдрома: современные стандарты. Тромбоз, гемостаз и реология. 2016;1(65):11-20 [Reshetnyak TM. Treatment of antiphospholipid syndrome: modern standarts. Tromboz, gemostaz i reologia. 2016;1(65):11-20 (In Russ.)].
5. Babin JL, Traylor KL, Witt DM. Laboratory monitoring of low-molecular-weight heparin and fondaparinux. Semin Thromb Hemost. 2017;43(3):261-9. https://doi.org/10.1055/s-0036-1581129
6. Chighizola CB, Moia M, Meroni PL. New oral anticoagulants in thrombotic antiphospholipid syndrome. Lupus. 2014;23(12):1279-82. https://doi.org/10.1177/0961203314540968
7. Сатыбалдыева М.А., Решетняк Т.М. Новые оральные антикоагулянты в терапии антифосфолипидного синдрома. Научно-практическая ревматология. 2016;54(2):219-26 [Satybaldyeva MA, Reshetnyak TM. New oral anticoagulants in the therapy of antiphospholipid syndrome. Rheumatology Science and Practice. 2016;54(2):219-26 (In Russ.)]. http://dx.doi.org/10.14412/1995-4484-2016-219-226
8. Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA. RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomized, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016;3(9):426-36. https://doi.org/10.1016/S2352-3026(16)30079-5
9. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29(2):288-91.
10. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.
11. Miyakis S,, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306. https://doi.org/10.1111/j.1538-7836.2006.01753.x
12. Решетняк Т.М. Антифосфолипидный синдром: диагностика и клинические проявления (лекция). Научно-практическая ревматология. 2014;52(1):56-71 [Reshetnyak TM. Antiphospholipid syndrome: diagnosis and clinical manifestations (a lecture). Rheumatology Science and Practice. 2014;52(1):56-71 (In Russ.)]. http://dx.doi.org/10. 14412/1995-4484-2014-56-71
13. Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, de Groot P, Lakos G, Lambert M, Meroni P, Ortel TL, Petri M, Rahman A, Roubey R, Sciascia S, Snyder M, Tebo AE, Tincani A, Willis R. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014;13:917-30. https://doi.org/10.1016/j.autrev. 2014.05.001
14. Pengo V, Banzato A, Denas G, Jose SP, Bison E, Hoxha A, Ruffatti A. Correct laboratory approach to APS diagnosis and monitoring. Autoimmun Rev. 2013;12:832-4. https://doi.org/10.1016/j.autrev.2012.11.008
15. Cередавкина Н.В., Решетняк Т.М. IX Европейский форум по антифосфолипидным антителам. Краткий обзор. Научно-практическая ревматология. 2014;52(1):115-21 [Seredavkina NV, Reshetnyak TM. The IX European forum on antiphospholipid antibodies. A brief review. Rheumatology Science and Practice. 2014;52(1):115-21 (In Russ.)]. http://dx.doi.org/10.14412/1995-4484-2014-115-121
16. Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev. 2013;12:752-7. https://doi.org/10.1016/j.autrev.2012.12.006
17. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S-e43S. https://doi.org/10.1378/chest.11-2291
18. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833-40.
19. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points. Chest. 2004;126(2):501-8.
20. Donath L, Lützner J, Werth S, Kuhlisch E, Hartmann A, Günther KP, Weiss N, Beyer-Westendorf J. Efficacy and safety of venous thromboembolism prophylaxis with fondaparinux or low molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery - findings from the ORTHO-TEP registry. Br J Clin Pharmacol. 2012;74(6):947-58. https://doi.org/10.1111/j.1365-2125.2012.04302.x
21. Moore TJ. Optimal dosing of rivaroxaban is undefined. BMJ. 2016;355:i5549. https://doi.org/10.1136/bmj.i5549
22. Joalland F, de Boysson H, Darnige L, Johnson A, Jeanjean C, Cheze S, Augustin A, Auzary C, Geffray L. Seronegative antiphospholipid syndrome, catastrophic syndrome, new anticoagulants: learning from a difficult case report. Rev Med Interne. (In French). 2014;35(11):752-6. https://doi.org/10.1016/j.revmed.2014.04.012
23. Holtan SG, Knox SK, Tefferi A. Use of fondaparinux in a patient with antiphospholipid antibody syndrome and heparin-associated thrombocytopenia. J Thromb Haemost. 2006;4(7):1632-4. https://doi.org/ 10.1111/j.1538-7836.2006.01961.x
24. Costa R, Fazal S, Kaplan RB, Spero J, Costa R. Successful plasma exchange combined with rituximab therapy in aggressive APS-related cutaneous necrosis. Clin Rheumatol. 2013;32(Suppl 1):S79-82. https://doi. org/10.1007/s10067-010-1506-3
25. Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb Res. 2007;119(3):385-8. https://doi.org/10.1016/j.thromres.2006. 03.008
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1. Nasonov EL. Antiphospholipidny sindrom. Moscow: Letterra, 2004 (In Russ.).
2. Kirienko AP, Panchenko EP, Andriyashkin VV. Venozny tromboz v praktike terapevta i hirurga. Moscow: Planida, 2012 (In Russ.).
3. Streiff MB, Agnelli G, Connors JM, Crowther M, Eichinger S, Lopes R, McBane RD, Moll S, Ansell J. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis. 2016;41(1):32-67. https://doi.org/10.1007/s11239-015-1317-0
4. Reshetnyak TM. Treatment of antiphospholipid syndrome: modern standarts. Tromboz, gemostaz i reologia. 2016;1(65):11-20 (In Russ.).
5. Babin JL, Traylor KL, Witt DM. Laboratory monitoring of low-molecular-weight heparin and fondaparinux. Semin Thromb Hemost. 2017;43(3):261-9. https://doi.org/10.1055/s-0036-1581129
6. Chighizola CB, Moia M, Meroni PL. New oral anticoagulants in thrombotic antiphospholipid syndrome. Lupus. 2014;23(12):1279-82. https://doi.org/10.1177/0961203314540968
7. Satybaldyeva MA, Reshetnyak TM. New oral anticoagulants in the therapy of antiphospholipid syndrome. Rheumatology Science and Practice. 2016;54(2):219-26 (In Russ.). http://dx.doi.org/10.14412/1995-4484-2016-219-226
8. Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA. RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomized, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol. 2016;3(9):426-36. https://doi.org/10.1016/S2352-3026(16)30079-5
9. Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002;29(2):288-91.
10. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J. CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.
11. Miyakis S,, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306. https://doi.org/10.1111/j.1538-7836.2006.01753.x
12. Reshetnyak TM. Antiphospholipid syndrome: diagnosis and clinical manifestations (a lecture). Rheumatology Science and Practice. 2014;52(1):56-71 (In Russ.). http://dx.doi.org/10. 14412/1995-4484-2014-56-71
13. Bertolaccini ML, Amengual O, Andreoli L, Atsumi T, Chighizola CB, Forastiero R, de Groot P, Lakos G, Lambert M, Meroni P, Ortel TL, Petri M, Rahman A, Roubey R, Sciascia S, Snyder M, Tebo AE, Tincani A, Willis R. 14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends. Autoimmun Rev. 2014;13:917-30. https://doi.org/10.1016/j.autrev. 2014.05.001
14. Pengo V, Banzato A, Denas G, Jose SP, Bison E, Hoxha A, Ruffatti A. Correct laboratory approach to APS diagnosis and monitoring. Autoimmun Rev. 2013;12:832-4. https://doi.org/10.1016/j.autrev.2012.11.008
15. Seredavkina NV, Reshetnyak TM. The IX European forum on antiphospholipid antibodies. A brief review. Rheumatology Science and Practice. 2014;52(1):115-21 (In Russ.) http://dx.doi.org/10.14412/1995-4484-2014-115-121
16. Comarmond C, Cacoub P. Antiphospholipid syndrome: from pathogenesis to novel immunomodulatory therapies. Autoimmun Rev. 2013;12:752-7. https://doi.org/10.1016/j.autrev.2012.12.006
17. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e24S-e43S. https://doi.org/10.1378/chest.11-2291
18. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833-40.
19. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points. Chest. 2004;126(2):501-8.
20. Donath L, Lützner J, Werth S, Kuhlisch E, Hartmann A, Günther KP, Weiss N, Beyer-Westendorf J. Efficacy and safety of venous thromboembolism prophylaxis with fondaparinux or low molecular weight heparin in a large cohort of consecutive patients undergoing major orthopaedic surgery - findings from the ORTHO-TEP registry. Br J Clin Pharmacol. 2012;74(6):947-58. https://doi.org/10.1111/j.1365-2125.2012.04302.x
21. Moore TJ. Optimal dosing of rivaroxaban is undefined. BMJ. 2016;355:i5549. https://doi.org/10.1136/bmj.i5549
22. Joalland F, de Boysson H, Darnige L, Johnson A, Jeanjean C, Cheze S, Augustin A, Auzary C, Geffray L. Seronegative antiphospholipid syndrome, catastrophic syndrome, new anticoagulants: learning from a difficult case report. Rev Med Interne. (In French). 2014;35(11):752-6. https://doi.org/10.1016/j.revmed.2014.04.012
23. Holtan SG, Knox SK, Tefferi A. Use of fondaparinux in a patient with antiphospholipid antibody syndrome and heparin-associated thrombocytopenia. J Thromb Haemost. 2006;4(7):1632-4. https://doi.org/ 10.1111/j.1538-7836.2006.01961.x
24. Costa R, Fazal S, Kaplan RB, Spero J, Costa R. Successful plasma exchange combined with rituximab therapy in aggressive APS-related cutaneous necrosis. Clin Rheumatol. 2013;32(Suppl 1):S79-82. https://doi. org/10.1007/s10067-010-1506-3
25. Harenberg J. Treatment of a woman with lupus and thromboembolism and cutaneous intolerance to heparins using fondaparinux during pregnancy. Thromb Res. 2007;119(3):385-8. https://doi.org/10.1016/j.thromres.2006. 03.008
1 ФГБНУ «Научно-исследовательский институт ревматологии им. В.А. Насоновой», лаборатория сосудистой ревматологии, клинико-диагностическое лабораторное отделение, Москва, Россия;
2 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, кафедра ревматологии, Москва, Россия
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N.V. Seredavkina 1, T.M. Reshetnyak 1,2, M.A. Satybaldyeva 1, L.N. Kashnikova 1, T.A. Temnikova 1, E.L. Nasonov 1
1 V.A. Nasonova Scientific and Research Institute of Rheumatology, laboratory of vascular rheumatology, clinical-diagnostical laboratory department, Moscow, Russia;
2 Federal State Budgetary Educational Institution of Further Professional Education "Russian Medical Academy of Continuous Professional Education" of the Ministry of Health of the Russian Federation, Moscow, Russia