Modern position of anticoagulants in acute pulmonary embolism: achievements, limitations, prospects

Abstract

Pulmonary embolism (PE) is the third most common cardiovascular disease after myocardial infarction and stroke, and one of the leading causes of death in Europe.

Aim. Analysis of the modern scientific base concerning the possibilities and limitations of use of anticoagulant therapy (ACT) at different stages of medical care in PE depending on risk stratification. The article reflects the position of modern Clinical guidelines, the results of recent studies and some controversial and unresolved issues of the ACT for PE.

Conclusion. Currently, a sufficient evidence base has been obtained in favor of the fact that the ACT increases the survival rate of patients with past PE even taking into account an increase in the frequency of hemorrhagic complications; the choice of therapy schemes for PE is based on the stratification of the risk of patients; the schemes of the ACT for the acute period, for the subsequent prevention of relapses of PE are developed, the evidence of the expediency of its further prolongation (a study of rivaroxaban at a dose of 10 mg for prolonged therapy) is obtained. Use of direct oral anticoagulants (DOAC) in patients with past PE has a more optimal efficacy/safety profile compared to vitamin K antagonists (VCA). However, not all the issues of the ACT for PE are solved, therefore the prospects for the study and application of the ACT in PE include: reasonability of obtaining substantiated data on use of DOAC after thrombolysis, in patients with reduced renal function, with antiphospholipid syndrome, with neoplastic diseases, and also for determination of exact periods of extended therapy. It is necessary to search for additional prognostic factors for PE, to study and register specific antidotes for DOAC (currently in the Russian Federation a specific antidote to dabigatran – Idarucizumab-registered); to increase the share of DOAC in the ACT as drugs with a proven best profile efficacy/safety compared to VCA.

Keywords

pulmonary embolism / PE / anticoagulant therapy / vitamin K antagonists / direct oral anticoagulant / new oral anticoagulant / risk stratification

References

[1] Konstantinides S, Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Endorsed by the European Respiratory Society (ERS). Eur Heart J. 2014;35: 3033-69. doi:10.1093/eurheartj/ehu283

[2] Konstantinides S., Torbicki A., Agnelli G., et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Endorsed by the European Respiratory Society (ERS) // Eur. Heart. J. 2014. Vol. 35. P. 3033-3069. doi:10.1093/eurheartj/ehu283

[3] Barbarash OL, Boytsov SA, Vaysman DSh, et al. Problemy otsenki pokazateley smertnosti ot otdelʹnykh prichin. Kompleksnyye problemy serdechno-sosudistykh zabolevaniy. 2018;7(2):6-9. (In Russ). doi:10/17802/2306-1278-2018-7-2-6-9

[4] Барбараш О.Л., Бойцов С.А., Вайсман Д.Ш., и др. Проблемы оценки показателей смертности от отдельных причин position statement // Комплексные проблемы сердечно-сосудистых заболеваний. 2018. Т. 7, №2. С. 6-9. doi:10/17802/ 2306-1278-2018-7-2-6-9

[5] Boytsov SA, Nikulina NN, Yakushin SS, et al. Patologo-anatomicheskoe issledovanie v analize smertnosti naseleniya ot serdechno-sosudistykh zabolevaniy. Arkhiv patologii. 2011;73(1):30-3. (In Russ).

[6] Бойцов С.А., Никулина Н.Н., Якушин С.С., и др. Патологоанатомическое исследование в анализе смертности населения от сердечно-сосудистых заболеваний // Архив патологии. 2011. Т. 73, №1. С. 30-33.

[7] Boytsov SA, Nikulina NN, Yakushin SS, et al. Mesto autopsii sredi sovremennykh metodov diagnostiki serdechno-sosudistykh zabolevaniy (po rezulʹtatam rossiyskogo mnogotsentrovogo ehpidemiologicheskogo issledovaniya zabolevaemosti, smertnosti, kachestva diagnostiki i lecheniya ostrykh form IBS «REZONANS»). Serdtse: zhurnal dlya praktikuyushchikh vrachey. 2010;9(4):231-3. (In Russ).

[8] Бойцов С.А., Никулина Н.Н., Якушин С.С., и др. Место аутопсии среди современных методов диагностики сердечно-сосудистых заболеваний (по результатам российского многоцентрового эпидемиологического исследования заболеваемости, смертности, качества диагностики и лечения острых форм ИБС «РЕЗОНАНС») // Сердце: журнал для практикующих врачей. 2010. Т. 9, №4 (54). С. 231-233.

[9] Vertkin AL, Rumyantsev MA, Skotnikov AS. Komorbidnostʹ v Klinicheskoy praktike. Chastʹ 2. Arkhiv vnutrenney meditsiny. 2011;2:20-4. (In Russ).

[10] Вёрткин А.Л., Румянцев М.А., Скотников А.С. Коморбидность в клинической практике. Часть 2 // Архивъ внутренней медицины. 2011. №2. С. 20-24.

[11] Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease. CHEST Guideline and Expert Panel Report. CHEST. 2016;149(2):315-52. doi:10.1016/j.chest.2016.08.1442

[12] Kearon C., Akl E.A., Ornelas J., et al. Antithrombotic Therapy for VTE Disease. CHEST Guideline and Expert Panel Report // CHEST. 2016. Vol. 149, №2. P. 315-352. doi:10.1016/j.chest.2016.08.1442

[13] Witt DM, Nieuwlaat R, Clark N P, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Advances. 2018;2(22):3257-91. doi:10.1182/bloodad-vances.2018024893

[14] Witt D.M., Nieuwlaat R., Clark N.P., et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy // Blood Advances. 2018. Vol. 2, №22. C. 3257-3291. doi:10. 1182/bloodadvances.2018024893

[15] Bokeriya LA, Zatevakhin II, Kiriyenko AI, et al. Rossiyskie klinicheskie rekomendatsii po diagnostike, lecheniyu i profilaktike venoznykh tromboehmbolicheskikh oslozhneniy (VTEHO). Flebologiya. 2015;9(4):2-52. (In Russ).

[16] Бокерия Л.А., Затевахин И.И., Кириенко А.И., и др. Российские клинические рекомендации по диагностике, лечению и профилактике венозных тромбоэмболических осложнений (ВТЭО) // Флебология. 2015. Т. 9, №4 (2). С. 2-52.

[17] Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402-14. doi:10. 1056/nejmc1406283

[18] Meyer G., Vicaut E., Danays T., et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism // N. Engl. J. Med. 2014. Vol. 370. P. 1402-1411. doi:10.1056/nejmc140628310

[19] Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the «MOPETT» Trial). Am J Cardiol. 2013;111(2): 273-7. doi:10.1016/j.amjcard.2012.09.027

[20] Sharifi M., Bay C., Skrocki L., et al. Moderate pulmonary embolism treated with thrombolysis (from the «MOPETT» Trial) // Am. J. Cardiol. 2013. Vol. 111, №2. P. 273-277. doi:10.1016/j. amjcard.2012.09.027

[21] Kropacheva ES, Borovkov NN, Vavilova TV, et al. Bystrye tempy nasyshcheniya varfarinom – prediktor razvitiya chrezmernoy gipokoagulyatsii. Modernizatsiya algoritma podbora dozy varfarina. Aterotromboz. 2015;1:74-86. (In Russ).

[22] Кропачева Е.С., Боровков Н.Н., Вавилова Т.В., и др. Быстрые темпы насыщения варфарином – предиктор развития чрезмерной гипокоагуляции. Модернизация алгоритма подбора дозы варфарина // Атеротромбоз. 2015. №1. С. 74-86.

[23] Agapov AB, Suchkov IA, Ryabkov AN. Direct oral anticoagulants in patients with deep vein thrombosis of the lower extremities. Science of the Young (Eruditio Juvenium). 2016;2:147-57. (In Russ).

[24] Агапов А.Б., Сучков И.А., Рябков А.Н. Прямые пероральные антикоагулянты в лечении пациентов с тромбозом глубоких вен нижних конечностей // Наука молодых (Eruditio Juvenium). 2016. №2. С. 147-157.

[25] Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361 (24):2342-52. doi:10.1056/nejmoa0906598

[26] Schulman S., Kearon C., Kakkar A.K., et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism // N. Engl. J. Med. 2009. Vol. 361, №24. P. 2342-2352. doi:10.1056/nejmoa0906598

[27] Schulman S, Kakkar AK, Goldhaber SZ, et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-72. doi:10.1161/circulatio-naha.113.004450

[28] Schulman S., Kakkar A.K., Goldhaber S.Z., et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis // Circulation. 2014. Vol. 129, №7. P. 764-772. doi:10.1161/ circulationaha.113.004450

[29] Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-510. doi:10.1056/nejmoa1007903

[30] Bauersachs R., Berkowitz S.D., Brenner B., et al. Oral rivaroxaban for symptomatic venous thromboembolism // N. Engl. J. Med. 2010. Vol. 363, №26. P. 2499-2510. doi:10.1056/nejmoa1007903

[31] Buller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97. doi:10.1056/nejmoa1113572

[32] Buller H.R., Prins M.H., Lensin A.W., et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism // N. Engl. J. Med. 2012. Vol. 366, №14. P. 1287-1297. doi:10.1056/nejmoa1113572

[33] Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799-808. doi: 10.1056/nejmoa1302507

[34] Agnelli G., Buller H.R., Cohen A., et al. Oral apixaban for the treatment of acute venous thromboembolism // N. Engl. J. Med. 2013. Vol. 369, №9. P. 799-808. doi:10.1056/nejmoa1302507

[35] Buller HR, Decousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369 (15):1406-15. doi:10.1056/NEJMoa1306638

[36] Buller H.R., Decousus H., Grosso M.A., et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism // N. Engl. J. Med. 2013. Vol. 369, №15. P. 1406-1415. doi:10. 1056/NEJMoa1306638

[37] Instruktsiya po meditsinskomu primeneniyu lekarstvennogo preparata Xarelto® 10 mg. Registratsionnyy nomer LSR-009820/09. (In Russ).

[38] Инструкция по медицинскому применению лекарственного препарата Ксарелто® 10 мг. Регистрационный номер ЛСР-009820/09.

[39] Instruktsiya po meditsinskomu primeneniyu lekarstvennogo preparata Xarelto® 15 or 20 mg. Registratsionnyy nomer LP-001457. (In Russ).

[40] Инструкция по медицинскому применению лекарственного препарата Ксарелто® 15 или 20 мг. Регистрационный номер ЛП-001457.

[41] Instruktsiya po meditsinskomu primeneniyu lekarstvennogo preparata Eliquis® 2,5 mg. Registratsionnyy nomer LP-001475-030212. (In Russ).

[42] Инструкция по медицинскому применению лекарственного препарата Эликвис® 2,5 мг. Регистрационный номер ЛП 001475-030212.

[43] Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330-93. doi:10.1093/ eurheartj/ehy136

[44] Steffel J., Verhamme P., Potpara T.S., et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation // Eur. Heart J. 2018. Vol. 39. P. 1330-1393. doi:10.1093/ eurheartj/ehy136

[45] Sharifi M, Bay C, Schwartz F, et al. Safe-dose thrombolysis plus rivaroxaban for moderate and severe pulmonary embolism: drip, drug, and discharge. Clin Cardiol. 2014;37(2):78-82. doi:10.1002/clc.22216

[46] Sharifi M., Bay C., Schwartz F., et al. Safe-dose thrombolysis plus rivaroxaban for moderate and severe pulmonary embolism: drip, drug, and discharge // Clin. Cardiol. 2014. Vol. 37, №2. P. 78-82. doi:10.1002/clc.22216

[47] Pengo V, Denas G, Zoppellaro G, et al. Rivaro-xaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132(13):1365 -71. doi:10.1182/blood-2018-04-848333

[48] Pengo V., Denas G., Zoppellaro G., et al. Rivaro-xaban vs warfarin in high-risk patients with antiphospholipid syndrome // Blood. 2018. Vol. 132, №13. P. 1365-1371. doi:10.1182/blood-2018-04-848333

[49] Carrier M, Prandoni P. Controversies in the management of cancer-associated thrombosis. Expert Rev Hematol. 2017;10:15-22. doi:10.1080/174740 86.2017.1257935

[50] Carrier M., Prandoni P. Controversies in the management of cancer-associated thrombosis // Expert Rev. Hematol. 2017. №10. P. 15-22. doi:10.1080/ 17474086.2017.1257935

[51] Young AM, Marshall A, Thirlwall J, et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). J Clin Oncol. 2018;36(20):2017-23. doi:10.1200/JCO.2018.78.8034

[52] Young A.M., Marshall A., Thirlwall J., et al. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D) // J. Clin. Oncol. 2018. Vol. 36, №20. P. 2017-2023. doi: 10.1200/ JCO.2018.78.8034

[53] Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018;378: 615-24. doi:10.1056/NEJMoa1711948

[54] Raskob G.E., van Es N., Verhamme P., et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism // N. Engl. J. Med. 2018. Vol. 378. P. 615-624. doi:10.1056/NEJMoa1711948

[55] Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer‐associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost. 2018;16:1891-4. doi:10.1111/jth.14219

[56] Khorana A.A., Noble S., Lee A.Y.Y., et al. Role of direct oral anticoagulants in the treatment of cancer‐associated venous thromboembolism: guidance from the SSC of the ISTH // J. Thromb. Haemost. 2018. №16. P. 1891-1894. doi:10.1111/jth.14219

[57] Kearon C, Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood. 2014;123:1794-801. doi:10.1182/ blood-2013-12-512681

[58] Kearon C., Akl E.A. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism // Blood. 2014. Vol. 123. P. 1794-1801. doi:10.1182/blood-2013-12-512681

[59] Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92(2):199-205. doi:10. 3324/haematol.10516

[60] Prandoni P., Noventa F., Ghirarduzzi A., et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients // Haematologica. 2007. Vol. 92, №2. P. 199-205. doi:10.3324/haematol.10516

[61] Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368(8):709-18. doi:10.1056/nejmoa1113697

[62] Schulman S., Kearon C., Kakkar A.K., et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism // N. Engl. J. Med. 2013. Vol. 368, №8. P. 709-718. doi:10.1056/nejmoa 1113697

[63] Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368(8):699-708. doi:10.1097/sa. 0b013e3182a495a4

[64] Agnelli G., Buller H.R., Cohen A., et al. Apixaban for extended treatment of venous thromboembolism // N. Engl. J. Med. 2013. Vol. 368, №8. P. 699-708. doi:10.1097/sa.0b013e3182a495a4

[65] Prins MH, Lensing AWA, Prandoni P, et al. Risk of recurrent venous thromboembolism according to baseline risk factor profiles. Blood Advances. 2018; 2:788-96. doi:10.1182/bloodadvances.2018017160

[66] Prins M.H., Lensing A.W.A., Prandoni P., et al. Risk of recurrent venous thromboembolism accor-ding to baseline risk factor profiles // Blood Advances. 2018. №2. P. 788-796. doi:10.1182/blood advances.2018017160

[67] Instruktsiya po meditsinskomu primeneniyu lekar-stvennogo preparata Warfarin Nycomed ® 2,5 mg. Registratsionnyy nomer LSR-006342/10. (In Russ).

[68] Инструкция по медицинскому применению лекарственного препарата Варфарин-Никомед® 2,5 мг. Регистрационный номер ЛСР-006342/10.

[69] Silva C, Fiumara K, Kachalia A. A Guide to Taking Warfarin. Available at https://www.mghpcs.org/ eed_portal/Documents/AMS/MGHAMSWarfarin

[70] Silva C., Fiumara K., Kachalia A. Руководство по приему варфарина. A Guide to Taking Warfarin (Russ). Доступно по: https://acforum-excellence.org /sites/default/files/Warfarin%20Patient%20Guide%20-%20Russian.pdf Ссылка активна на 14 декабря 2018.

[71] Guide_Russian.pdf Accessed: 15 Jan 2019. (In Russ).

[72] Лукьянов М.М., Бойцов С.А., Якушин С.С., и др. Сочетанные сердечно-сосудистые заболевания и антигипертензивное лечение у больных артериальной гипертонией в амбулаторно-поликлинической практике (по данным регистра РЕКВАЗА) // Рациональная фармакотерапия в кардиологии. 2016. Т. 12, №1. С. 4-15.

[73] Luk’yanov MM, Boytsov SA, Yakushin SS, et al. Сoncomitant cardiovascular diseases and antihypertensive treatment in outpatient practice. Ratsio-nal’naya farmakoterapiya v kardiologii. 2016; 12(1):4-15. (In Russ).

[74] Бельдиев С.Н., Медведева И.В., Платонов Д.Ю. Лекарственные взаимодействия новых пероральных антикоагулянтов: внутри и вне ячеек таблицы // Рациональная фармакотерапия в кардиологии. 2017. T. 13, №5. C. 716-724. doi:10. 20996/1819-6446-2017-135-716-724

[75] Bel’diyev SN, Medvedeva IV, Platonov DYu. Drug interactions of new oral anticoagulants: inside and outside the table cells. Ratsional’naya farmakoterapiya v kardiologii. 2017;13(5):716-24. (In Russ). doi:10.20996/1819-6446-2017-135-716-724

[76] Якушева Е.Н., Черных И.В., Щулькин А.В., и др. Методика определения принадлежности лекарственных средств к числу субстратов Гликопротеина-Р // Российский медико-биологичес-кий вестник имени академика И.П. Павлова. 2015. Т. 23, №3. С. 49-53.

[77] Yakusheva EN, Chernykh IV, Shchul’kin AV, et al. Methods of identification of drugs as P-glyco-protein substrates. I.P. Pavlov Russian Medical

[78] Щулькин А.В., Якушева Е.Н., Попова Н.М. Роль Гликопротеина-P в рациональной фармакотерапии в кардиологии // Рациональная фармакотерапия в кардиологии. 2013. Т. 9, №6. С. 701-707.

[79] Biological Herald. 2015;23(3):49-53. (In Russ).

[80] Инструкция по медицинскому применению лекарственного препарата Праксбайнд® 2,5 г. Регистрационный номер ЛП-005017.

[81] Shchul’kin AV, Yakusheva EN, Popova NM. The role of Glycoprotein-P in rational pharmacotherapy in cardiology. Ratsional’naya farmakoterapiya v kardiologii. 2013;9(6):701-7. (In Russ).

[82] Хорев Н.Г., Момот А.П., Конькова В.О. Антидоты новых прямых оральных антикоагулянтов. Ангиология и сосудистая хирургия. 2016. Т. 22. С. 177-183.

[83] Instruktsiya po meditsinskomu primeneniyu lekar-stvennogo preparata Praxbaynd® 2,5 g. Registra-tsionnyy nomer LP-005017. (In Russ).

[84] Khorev NG, Momot AP, Konʹkova VO. Antidotes to novel direct oral anticoagulants. Angiology and Vascular Surgery. 2016;22:177-83. (In Russ).

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Terekhovskaya Y.V., Okorokov V.G., Nikulina N.N.