The ClinicianThe ClinicianКлиницист1818-83382412-8775Publishing House ABV Press25410.17650/1818-8338-2016-10-2-10-17EDITORIALРЕДАКЦИОННАЯ СТАТЬЯTHE ROLE OF ANTICOAGULATION THERAPY IN PATIENTS WITH PROSTHETIC HEART VALVESРОЛЬ АНТИКОАГУЛЯНТНОЙ ТЕРАПИИ В ЛЕЧЕНИИ ПАЦИЕНТОВ С ПРОТЕЗИРОВАННЫМИ КЛАПАНАМИ СЕРДЦАShostakN. A.ШостакН. А.
Russian Federation

Department of faculty therapy named after academician A.I. Nesterov,

1 Ostrovityanova St., Moscow, 117997

Кафедра факультетской терапии им. акад. А.И. Нестерова,

117997, Москва, ул. Островитянова, 1

KlimenkoA. A.КлименкоА. А.
Russian Federation

Department of faculty therapy named after academician A.I. Nesterov,

1 Ostrovityanova St., Moscow, 117997

Кафедра факультетской терапии им. акад. А.И. Нестерова,

117997, Москва, ул. Островитянова, 1

AndriyashkinaD. Y.АндрияшкинаД. Ю.
Russian Federation

Department of faculty therapy named after academician A.I. Nesterov,

1 Ostrovityanova St., Moscow, 117997

Кафедра факультетской терапии им. акад. А.И. Нестерова,

117997, Москва, ул. Островитянова, 1

andryashkina.darya@yandex.ruKondrashovA. A.КондрашовА. А.
Russian Federation

Department of faculty therapy named after academician A.I. Nesterov,

1 Ostrovityanova St., Moscow, 117997

Кафедра факультетской терапии им. акад. А.И. Нестерова,

117997, Москва, ул. Островитянова, 1

NovikovaA. V.НовиковаА. В.
Russian Federation

Department of faculty therapy named after academician A.I. Nesterov,

1 Ostrovityanova St., Moscow, 117997

Кафедра факультетской терапии им. акад. А.И. Нестерова,

117997, Москва, ул. Островитянова, 1

State Budgetary Educational Institution of Higher Professional Education “Pirogov Russian National Research Medical University” of the Ministry of Health of RussiaФГБОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России1504201610210171609201616092016Copyright ©; 2016, Shostak N.A., Klimenko A.A., Andriyashkina D.Y., Kondrashov A.A., Novikova A.V.Copyright ©; 2016, Шостак Н.А., Клименко А.А., Андрияшкина Д.Ю., Кондрашов А.А., Новикова А.В.2016Shostak N.A., Klimenko A.A., Andriyashkina D.Y., Kondrashov A.A., Novikova A.V.Шостак Н.А., Клименко А.А., Андрияшкина Д.Ю., Кондрашов А.А., Новикова А.В.https://creativecommons.org/licenses/by/4.0https://klinitsist.abvpress.ru/Klin/article/view/254

Cardiac surgery is the only radical method of treatment of valvular defects (congenital or acquired): valve preservation procedures or prosthetics operations. 250 000 – 280 000 valve prostheses are implanted every year worldwide, while the number of prosthetic valves operation increases by an average of 5–7 % per year (biological prostheses – 8–11 %, mechanical prostheses – 3–5 %). Selection of biological or mechanical types of prosthesis, its location, the presence of associated risk factors for embolic events, such as atrial fibrillation, previous embolism, left ventricular dysfunction, hypercoagulable states determine patient management tactics. Particularly high risk of prosthetic thrombosis and thromboembolic complications can be seen in case of mechanical prosthesis implantation. Numerous prospective and retrospective clinical studies have proven high effectiveness of anticoagulants for reduction the risk of cardioembolic complications. The degree of anticoagulation (optimal international normalized ratio (INR)) is determined by risk factors for prosthetic thrombosis and thromboembolic complications in a patient, as well as thrombogenicity of the prosthesis by itself; INR may range from 2.5 to 4.0. International recommendations take into account the presence/absence of additional risk factors for thromboembolism, and based on warfarin administration with the achievement of target INR values combined with low-dose aspirin. Administration of novel direct oral anticoagulation remedies in patients with prosthetic heart valves has not been studied sufficiently up to date and is contraindicated. Thus, warfarin currently is a drug of choice for the prevention of thromboembolic complications in patients with prosthetic heart valves.

Единственным радикальным методом лечения пороков клапанного аппарата сердца (приобретенных или врожденных) является кардиохирургическое вмешательство: клапаносохраняющие операции или протезирование. Ежегодно в мире имплантируется от 250 тыс. до 280 тыс. клапанных протезов, и число операций по протезированию клапанов увеличивается в среднем на 5–7 % в год (биологическими протезами – на 8–11 %, механическими – на 3–5 %). Выбор биологического или механического типа протеза, его локализация, наличие сопутствующих факторов риска эмболий, таких как фибрилляция предсердий, предшествующие тромбоэмболии, дисфункция левого желудочка, гиперкоагуляционные состояния, определяют тактику ведения пациента. Особенно высокий риск тромбозов протезов и тромбоэмболических осложнений наблюдается при установке протезов механического типа. Многочисленные проспективные и ретроспективные клинические исследования доказали высокую эффективность непрямых антикоагулянтов для снижения риска кардиоэмболических осложнений. Степень гипокоагуляции (оптимальное международное нормализованное отношение (МНО)) определяется факторами риска развития тромбоза протезов и тромбо- эмболических осложнений у больного, а также тромбогенностью самого протеза; МНО может составлять от 2,5 до 4,0. Международные рекомендации учитывают наличие/отсутствие дополнительных факторов риска тромбоэмболий и основаны на назначении варфарина с достижением целевых значений МНО в сочетании с низкими дозами аспирина. Применение новых прямых оральных антикоагулянтов у пациентов с протезированными клапанами сердца на сегодняшний день недостаточно изучено и противопоказано. Таким образом, в настоящее время именно варфарин является препаратом выбора для профилактики тромбоэмболических осложнений у пациентов с протезированными клапанами сердца.

valvular heart diseaseacquired heart diseaserheumatic heart diseaseprosthetic heart valvesthromboembolic complicationscardiogenic embolismblood clot in the left atriumspontaneous echo contrasting in the left atriumatrial fibrillationanticoagulant therapyvitamin K antagonistsnovel direct oral anticoagulantswarfarinклапанная болезнь сердцаприобретенные пороки сердцаревматическая болезнь сердцапротезирование клапанов сердцатромбоэмболические осложнениякардиогенная эмболиятромб в полости левого предсердияспонтанное эхоконтрастирование в левом предсердиифибрилляция предсердийантикоагулянтная терапияантагонисты витамина Кновые прямые оральные антикоагулянтыварфарин1. Bonow R.O., Carabello B.А., Chatterjee K. et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48(3):e1–148.Bonow R.O., Carabello B.А., Chatterjee K. et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006;48(3):e1–148.2. Nkomo V.T., Gardin J.M., Skelton T.N. et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368(9540):1005–11.Nkomo V.T., Gardin J.M., Skelton T.N. et al. Burden of valvular heart diseases: a population-based study. Lancet 2006;368(9540):1005–11.3. Шостак Н.А., Карпова Н.Ю., Рашид М.А. Пискунов Д.В. Аортальные пороки в практике ревматолога: аортальный стеноз. Consilium medicum 2003;11(5):620–3. [Shostak N.А., Karpovа N.Y., Rashid М.А. Piskunov D.V. Аоrtal diseases in the rheumatologist’s practice: аоrtic stenosis. Consilium medicum 2003;11(5): 620–3. (In Russ.)].Шостак Н.А., Карпова Н.Ю., Рашид М.А. Пискунов Д.В. Аортальные пороки в практике ревматолога: аортальный стеноз. Consilium medicum 2003;11(5):620–3. [Shostak N.А., Karpovа N.Y., Rashid М.А. Piskunov D.V. Аоrtal diseases in the rheumatologist’s practice: аоrtic stenosis. Consilium medicum 2003;11(5): 620–3. (In Russ.)].4. Otto C.M., Prendergast B. Aortic-valve stenosis – from patients at risk to severe valve obstruction. N Engl J Med 2014;371(8):744-56.Otto C.M., Prendergast B. Aortic-valve stenosis – from patients at risk to severe valve obstruction. N Engl J Med 2014;371(8):744-56.5. Thourani V.H., Myung R., Kilgo P. et al. Long-term outcomes after isolated aortic valve replacement in octogenarians: a modern perspective. Ann Thorac Surg 2008;86(5): 1458–64.Thourani V.H., Myung R., Kilgo P. et al. Long-term outcomes after isolated aortic valve replacement in octogenarians: a modern perspective. Ann Thorac Surg 2008;86(5): 1458–64.6. Ivanoviс B., Tadic M., Dincic D. The effects of arterial hypertension on aortic valve stenosis. Vojnosanit Pregl 2010;67(7):588–92.Ivanoviс B., Tadic M., Dincic D. The effects of arterial hypertension on aortic valve stenosis. Vojnosanit Pregl 2010;67(7):588–92.7. Petty G.W., Khandheria B.K., Whisnant J.P. et al. Predictors of cerebrovascular events and death among patients with valvular heart disease: A population-based study. Stroke 2000;31(11):2628–35.Petty G.W., Khandheria B.K., Whisnant J.P. et al. Predictors of cerebrovascular events and death among patients with valvular heart disease: A population-based study. Stroke 2000;31(11):2628–35.8. Wood P. An appreciation of mitral stenosis, I: clinical features. Br Med J 1954;1(4870): 1051–63.Wood P. An appreciation of mitral stenosis, I: clinical features. Br Med J 1954;1(4870): 1051–63.9. Ellis L.B., Harken D.E. Arterial embolization in relation to mitral valvuloplasty. Am Heart J 1961;62:611–20.Ellis L.B., Harken D.E. Arterial embolization in relation to mitral valvuloplasty. Am Heart J 1961;62:611–20.10. Sanada J., Komaki S., Sannou K. et al. Significance of atrial fibrillation, left atrial thrombus and severity of stenosis for risk of systemic embolism in patients with mitral stenosis. J Cardiol 1999;33(1):1–5.Sanada J., Komaki S., Sannou K. et al. Significance of atrial fibrillation, left atrial thrombus and severity of stenosis for risk of systemic embolism in patients with mitral stenosis. J Cardiol 1999;33(1):1–5.11. Deverall P.B., Olley P.M., Smith D.R. еt al. Incidence of embolism before and after mitral valvotomy. Thorax 1968;23(5):530–6.Deverall P.B., Olley P.M., Smith D.R. еt al. Incidence of embolism before and after mitral valvotomy. Thorax 1968;23(5):530–6.12. Szekely P. Systemic embolization and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 1964;1(5392): 1209–12.Szekely P. Systemic embolization and anticoagulant prophylaxis in rheumatic heart disease. Br Med J 1964;1(5392): 1209–12.13. Levine H.J. Which atrial fibrillation patients should be on chronic anticoagulation? J Cardiovasc Med 1981;6:483–7.Levine H.J. Which atrial fibrillation patients should be on chronic anticoagulation? J Cardiovasc Med 1981;6:483–7.14. Hwang J.J., Shyu K.G., Hsu K.L. et al. Significant mitral regurgitation is protective against left atrial spontaneous echo contrast formation, but not against systemic embolism. Chest 1994;106(1):8–12.Hwang J.J., Shyu K.G., Hsu K.L. et al. Significant mitral regurgitation is protective against left atrial spontaneous echo contrast formation, but not against systemic embolism. Chest 1994;106(1):8–12.15. Dewar H.A., Weightman D. A study of embolism in mitral valve disease and atrial fibrillation. Br Heart J 1983;49(2):133–40.Dewar H.A., Weightman D. A study of embolism in mitral valve disease and atrial fibrillation. Br Heart J 1983;49(2):133–40.16. Wada Y., Mizushige K., Ohmori K. Prevention of cerebral thromboembolism by low-dose anticoagulant therapy in atrial fibrillation with mitral regurgitation. J Cardiovasc Pharmacol 2001;37(4): 422–6.Wada Y., Mizushige K., Ohmori K. Prevention of cerebral thromboembolism by low-dose anticoagulant therapy in atrial fibrillation with mitral regurgitation. J Cardiovasc Pharmacol 2001;37(4): 422–6.17. Carter A.B. Prognosis of cerebral embolism. Lancet 1965;2(7411):514–9.Carter A.B. Prognosis of cerebral embolism. Lancet 1965;2(7411):514–9.18. Cayly M., Kanadasi I.M., Demir M. Acartürk E. Mitral annular systolic velocity reflects the left atrial appendage function in mitral stenosis. Echocardiography 2006;23(7):546–52.Cayly M., Kanadasi I.M., Demir M. Acartürk E. Mitral annular systolic velocity reflects the left atrial appendage function in mitral stenosis. Echocardiography 2006;23(7):546–52.19. Rastegar R., Harnich D.J., Weidemann P. et al. Spontaneous echo contrast videodensity is flow-related and is dependent on the relative concentrations of fibrinogen and red blood cells. J Am Coll Cardiol 2003;41(4):603–10.Rastegar R., Harnich D.J., Weidemann P. et al. Spontaneous echo contrast videodensity is flow-related and is dependent on the relative concentrations of fibrinogen and red blood cells. J Am Coll Cardiol 2003;41(4):603–10.20. Fleming H.A. Anticoagulants in rheumatic heart-disease. Lancet 1971;2(7722):486.Fleming H.A. Anticoagulants in rheumatic heart-disease. Lancet 1971;2(7722):486.21. Gilon D., Buonanno F.S., Joffe M.M. et al. Lack of evidence of an association between mitral-valve prolapse and stroke in young patients. N Engl J Med 1999;341(1):8–13.Gilon D., Buonanno F.S., Joffe M.M. et al. Lack of evidence of an association between mitral-valve prolapse and stroke in young patients. N Engl J Med 1999;341(1):8–13.22. Chan K.L., Dumesnil J.G., Cujec B. et al. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol 2003;42(5):775–80.Chan K.L., Dumesnil J.G., Cujec B. et al. A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol 2003;42(5):775–80.23. Adams G.F., Merrett J.D., Hutchinson W.M., Pollock A.M. Cerebral embolism and mitral stenosis: survival with and without anticoagulants. J Neurol Neurosurg Psychiatry 1974;37(4):378–83.Adams G.F., Merrett J.D., Hutchinson W.M., Pollock A.M. Cerebral embolism and mitral stenosis: survival with and without anticoagulants. J Neurol Neurosurg Psychiatry 1974;37(4):378–83.24. Fleming H.A., Bailay S.M. Mitral valve disease, systemic embolism and anticoagulation. Postgrad Med J 1971;47(551):599–604.Fleming H.A., Bailay S.M. Mitral valve disease, systemic embolism and anticoagulation. Postgrad Med J 1971;47(551):599–604.25. Perez-Gomez F., Salvador A., Zumalde J. et al. Effect of antithrombotic therapy in patients with mitral stenosis and atrial fibrillation: a sub-analysis of NASPEAF randomized trial. Eur Heart J 2006;27(8):960–7.Perez-Gomez F., Salvador A., Zumalde J. et al. Effect of antithrombotic therapy in patients with mitral stenosis and atrial fibrillation: a sub-analysis of NASPEAF randomized trial. Eur Heart J 2006;27(8):960–7.26. Silaruks S., Thinkhamrop B., Tantikosum W. et al. A prognostic model for predicting the disappearance of left atrial thrombi among candidates for percutaneous transvenous mitral commissurotomy. J Am Coll Cardiol 2002;39(5):886–91.Silaruks S., Thinkhamrop B., Tantikosum W. et al. A prognostic model for predicting the disappearance of left atrial thrombi among candidates for percutaneous transvenous mitral commissurotomy. J Am Coll Cardiol 2002;39(5):886–91.27. Nishimura R.A., Otto C.M., Bonow R.O. et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(23):521–643.Nishimura R.A., Otto C.M., Bonow R.O. et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(23):521–643.28. Supino P.G., Borer J.S., Yin A. The epidemiology of valvular heart disease: an emerging public health problem. Adv Cardiol 2002;39:1–6.Supino P.G., Borer J.S., Yin A. The epidemiology of valvular heart disease: an emerging public health problem. Adv Cardiol 2002;39:1–6.29. Pibarot P., Dumesnil J.G. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation 2009;119(7):1034–48.Pibarot P., Dumesnil J.G. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation 2009;119(7):1034–48.30. Butany J., Fayet C., Ahluwalia M.S. et al. Biological replacement heart valves. Identification and evaluation. Cardiovasc Pathol 2003;12(3):119–39.Butany J., Fayet C., Ahluwalia M.S. et al. Biological replacement heart valves. Identification and evaluation. Cardiovasc Pathol 2003;12(3):119–39.31. Grzymala-Lubanski B., Labaf A., Englund E. et al. Mechanical heart valve prosthesis and warfarin - treatment quality and prognosis. Thromb Res 2014;133(5):795–8.Grzymala-Lubanski B., Labaf A., Englund E. et al. Mechanical heart valve prosthesis and warfarin - treatment quality and prognosis. Thromb Res 2014;133(5):795–8.32. Бокерия Л.А. Гудкова Р.Г. Сердечно-сосудистая хирургия – 2008. Болезни и врожденные аномалии системы кровообращения. М.: НЦССХ им. А.Н. Бакулева РАМН, 2009. [Bokeria L.А. Gudkovа R.G. Сardio-vascular surgery – 2008. Diseases and inborn anomalies of the blood circulation system. Мoscow: NTSSK im. A.N. Bakuleva RAMN, 2009. (In Russ.)].Бокерия Л.А. Гудкова Р.Г. Сердечно-сосудистая хирургия – 2008. Болезни и врожденные аномалии системы кровообращения. М.: НЦССХ им. А.Н. Бакулева РАМН, 2009. [Bokeria L.А. Gudkovа R.G. Сardio-vascular surgery – 2008. Diseases and inborn anomalies of the blood circulation system. Мoscow: NTSSK im. A.N. Bakuleva RAMN, 2009. (In Russ.)].33. Константинов Б.А., Картошкин В.М., Евдокимов С.В. и др. Результаты лабораторных и клинических испытаний новых отечественных клапанов сердца модели ЛИКС-2. Грудная и сердечно-сосудистая хирургия 1989;(2):12–7. [Konstantnov B.А., Kartoshkin V.М., Еvdokimov С.В. et al. Results of laboratory and clinical tests of new national heart valves of LIKS -2 model. Grudnaya i serdechno-sosudistaya khirurgiya = Thoracic and Cardiovascular Surgery 1989;(2):12–7. (In Russ.)].Константинов Б.А., Картошкин В.М., Евдокимов С.В. и др. Результаты лабораторных и клинических испытаний новых отечественных клапанов сердца модели ЛИКС-2. Грудная и сердечно-сосудистая хирургия 1989;(2):12–7. [Konstantnov B.А., Kartoshkin V.М., Еvdokimov С.В. et al. Results of laboratory and clinical tests of new national heart valves of LIKS -2 model. Grudnaya i serdechno-sosudistaya khirurgiya = Thoracic and Cardiovascular Surgery 1989;(2):12–7. (In Russ.)].34. Орловский П.И., Гриценко В.В., Юхнев А.Д. и др. Искусственные клапаны сердца. Под ред. Ю.Л. Шевченко. СПб: ОЛМА МедиаГрупп, 2007. [Оrlovsky P.I., Gritsenko V.V., Yuhnev А.D. et al. Artificial heart valves. Ed. by Y.L. Shevchenko. Saint Petersburg: ОLМА МеdiaGroup, 2007. (In Russ.)].Орловский П.И., Гриценко В.В., Юхнев А.Д. и др. Искусственные клапаны сердца. Под ред. Ю.Л. Шевченко. СПб: ОЛМА МедиаГрупп, 2007. [Оrlovsky P.I., Gritsenko V.V., Yuhnev А.D. et al. Artificial heart valves. Ed. by Y.L. Shevchenko. Saint Petersburg: ОLМА МеdiaGroup, 2007. (In Russ.)].35. O’Brein M.F., Stafford E.G., Gardner M.A. et al. Allograft aortic valve replacement: long-term follow-up. Ann Thorac Surg 1995;60(2 Suppl):S65–70.O’Brein M.F., Stafford E.G., Gardner M.A. et al. Allograft aortic valve replacement: long-term follow-up. Ann Thorac Surg 1995;60(2 Suppl):S65–70.36. Salem D.N., O’Gara P.T., Madias C. et al. Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):593S–629S.Salem D.N., O’Gara P.T., Madias C. et al. Valvular and structural heart disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):593S–629S.37. Massel D.R., Little S.H. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev 2013;7:CD003464.Massel D.R., Little S.H. Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev 2013;7:CD003464.38. De Caterina R., Camm A.J. What is “valvular” atrial fibrillation? A reappraisal. Eur Heart J 2014;35(47):3328–35.De Caterina R., Camm A.J. What is “valvular” atrial fibrillation? A reappraisal. Eur Heart J 2014;35(47):3328–35.39. Regitz-Zagrosek V., Blomstrom L.C., Borghi C. et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011;32(24):3147–97.Regitz-Zagrosek V., Blomstrom L.C., Borghi C. et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J 2011;32(24):3147–97.40. Horstkotte D., Scharf R.E., Schultheiss H.P. Intracardiac thrombosis: patient-related and device-related factors. J Heart Valve Dis 1995;4(2):114–20.Horstkotte D., Scharf R.E., Schultheiss H.P. Intracardiac thrombosis: patient-related and device-related factors. J Heart Valve Dis 1995;4(2):114–20.41. Pruefer D., Dahm M., Dohmen G. Intensity of oral anticoagulation after implantation of St. Jude Medical mitral or multiple valve replacement: lessons learned from GELIA (GELIA 5). Eur Heart J 2001;3(Suppl Q):Q39–Q43.Pruefer D., Dahm M., Dohmen G. Intensity of oral anticoagulation after implantation of St. Jude Medical mitral or multiple valve replacement: lessons learned from GELIA (GELIA 5). Eur Heart J 2001;3(Suppl Q):Q39–Q43.42. Hering D., Piper C., Bergemann R. et al. Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German Experience With Low-Intensity Anticoagulation Study. Chest 2005;127(1):53–9.Hering D., Piper C., Bergemann R. et al. Thromboembolic and bleeding complications following St. Jude Medical valve replacement: results of the German Experience With Low-Intensity Anticoagulation Study. Chest 2005;127(1):53–9.43. Aramendi J.I., Mestres C.A., Martinez-Leon J. et al. Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (trac): prospective, randomized, co-operative trial. Eur J Cardiothorac Surg 2005;27(5):854–60.Aramendi J.I., Mestres C.A., Martinez-Leon J. et al. Triflusal versus oral anticoagulation for primary prevention of thromboembolism after bioprosthetic valve replacement (trac): prospective, randomized, co-operative trial. Eur J Cardiothorac Surg 2005;27(5):854–60.44. Heras M., Chesebro J.H., Fuster V. et al. High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol 1995;25(5):1111–9.Heras M., Chesebro J.H., Fuster V. et al. High risk of thromboemboli early after bioprosthetic cardiac valve replacement. J Am Coll Cardiol 1995;25(5):1111–9.45. Suri R.M., Thourani V.H., He X. et al. Variation in warfarin thromboprophylaxis after mitral valve repair: does equipoise exist and is a randomized trial warranted? Ann Thorac Surg 2013;95(6):1991–8.Suri R.M., Thourani V.H., He X. et al. Variation in warfarin thromboprophylaxis after mitral valve repair: does equipoise exist and is a randomized trial warranted? Ann Thorac Surg 2013;95(6):1991–8.46. Eikelboom J.W., Connolly S.J., Brueckmann M. et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369(13): 1206–14.Eikelboom J.W., Connolly S.J., Brueckmann M. et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013;369(13): 1206–14.47. Price J., Hynes M., Labinaz M. et al. Mechanical valve thrombosis with dabigatran. J Am Coll Cardiol 2012;60(17):1710–1.Price J., Hynes M., Labinaz M. et al. Mechanical valve thrombosis with dabigatran. J Am Coll Cardiol 2012;60(17):1710–1.48. Stewart R.A., Astell H., Young L., White H.D. Thrombosis on a Mechanical Aortic Valve whilst Anti-coagulated With Dabigatran. Heart Lung Circ 2012;21(1):53–5.Stewart R.A., Astell H., Young L., White H.D. Thrombosis on a Mechanical Aortic Valve whilst Anti-coagulated With Dabigatran. Heart Lung Circ 2012;21(1):53–5.49. Van de Werf F., Brueckmann M., Connolly S.J. et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatranetexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J 2012;163(6):931–7.Van de Werf F., Brueckmann M., Connolly S.J. et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatranetexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J 2012;163(6):931–7.50. Kaeberich A., Reindl I., Raaz U. et al. Comparison of unfractionated heparin, lowmolecular-weight heparin, low-dose and highdose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Thromb Thrombolysis 2011;32(4):417–25.Kaeberich A., Reindl I., Raaz U. et al. Comparison of unfractionated heparin, lowmolecular-weight heparin, low-dose and highdose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Thromb Thrombolysis 2011;32(4):417–25.51. Avezum A., Lopes R.D. Schulte P.J. et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation 2015;132(8):624–32.Avezum A., Lopes R.D. Schulte P.J. et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation 2015;132(8):624–32.52. Laffort P., Roudaut R., Roques X. et al. Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude medical prosthesis: a clinical and transesophageal echocardiographic study. J Am Coll Cardiol 2000;35(3):739–46.Laffort P., Roudaut R., Roques X. et al. Early and long-term (one-year) effects of the association of aspirin and oral anticoagulant on thrombi and morbidity after replacement of the mitral valve with the St. Jude medical prosthesis: a clinical and transesophageal echocardiographic study. J Am Coll Cardiol 2000;35(3):739–46.53. Pengo V., Palareti G., Cucchini U., et al. Low-intensity oral anticoagulant plus low-dose aspirin during the first six months versus standard-intensity oral anticoagulant therapy after mechanical heart valve replacement: a pilot study of low-intensity warfarin and aspirin in cardiac prostheses (LIWACAP). Clin Appl Thromb Hemost 2007;13(3):241–8.Pengo V., Palareti G., Cucchini U., et al. Low-intensity oral anticoagulant plus low-dose aspirin during the first six months versus standard-intensity oral anticoagulant therapy after mechanical heart valve replacement: a pilot study of low-intensity warfarin and aspirin in cardiac prostheses (LIWACAP). Clin Appl Thromb Hemost 2007;13(3):241–8.54. Altman R., Boullon F., Rouvier J. et al. Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. J Thorac Cardiovasc Surg 1976;72(1):127–9.Altman R., Boullon F., Rouvier J. et al. Aspirin and prophylaxis of thromboembolic complications in patients with substitute heart valves. J Thorac Cardiovasc Surg 1976;72(1):127–9.55. Windram J.D., Colman J.M., Wald R.M. et al. Valvular heart disease in pregnancy. Best Pract Res Clin Obstet Gynaecol 2014;28(4):507–18.Windram J.D., Colman J.M., Wald R.M. et al. Valvular heart disease in pregnancy. Best Pract Res Clin Obstet Gynaecol 2014;28(4):507–18.56. Vitale N., De Feo M., De Santo L.S. et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33(6): 1637–41.Vitale N., De Feo M., De Santo L.S. et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999;33(6): 1637–41.57. Bates S.M., Greer I.A. Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141 (2 Suppl):e691S–736S.Bates S.M., Greer I.A. Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141 (2 Suppl):e691S–736S.58. Vahanian A., Baumgartner H., Bax J. et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28(2): 230–68.Vahanian A., Baumgartner H., Bax J. et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28(2): 230–68.