Experience in the treatment of patients with pulmonary embolism using apixaban and ultrasound inhalations of unfractionated heparin

Introduction. Pulmonary embolism (PE) is one of the leading causes of death even in hospitalized patients. The standard treatment results are disappointing. Since 2004, we have tested a new method for the treatment of hemodynamically insignificant PE (own patent RU2224525C1) by using unfractionated heparin (UFH) in ultrasound inhalations with a nebulizer, since 2014 – in combination with apixaban. Aim. To improve the treatment of PE. Materials and methods. The hospital mortality rate of 713 patients of the cardiac intensive care unit with hemodynamically insignificant PE  (from January 1, 2002  to December 31, 2017) was studied. Since 2004, patients have received ultrasound UFH (5000 units twice a day). Since 2014, nebulased UFH has been supplemented with the use of apixaban (10 mg twice a day for 7 days and 5 mg twice a day thereafter). Results and discussion. There is a distinct tendency to the PE hospital mortality decrease, coinciding with the nebulased UFH use (illustrated by a diagram). Neither the systemic bleeding nor the heparin-induced thrombocytopenia were observed. Clinical cases show first reduction of  perfusion disorders are seeing scintigraphicaly in  7  days. Unlike LMWH UFH is recommended in severe kidney damage and obesity, thus ultrasound technique has advantages in such patients. Conclusions. Nebulased UFH is an available, simple, safe and effective in treatmtnt of hemodynamically insignificant PE, especially with the use of apixaban. A real improvement in lung perfusion takes 1 week, as shown scintigraphically.

1. Konstantinides S.V., Torbicki A., Agnelli G., Danchin N., Fitzmaurice D., Galiè N. et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033–3069. https://doi.org/10.1093/eurheartj/ehu283.

2. Konstantinides S.V., Meyer G., Becattini C., Bueno H., Geersing G.J., Harjola V.P. et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543–603. https://doi.org/10.1093/eurheartj/ehz405.

3. Chazova I.E., Martynyuk T.V., Valieva Z.S., Azizov V.A., Akchurin R.S., Ansheles A.A. et al. Eurasian association of cardiology (EAC) guidelines for the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (2020). Eurasian Heart Journal. 2021;(1):6–43. (In Russ.) https://doi.org/10.38109/2225-1685-2021-1-6-43.

4. Wan S., Quinlan D.J., Agnelli G., Eikelboom J.W. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004;110(6):744–749. https://doi.org/10.1161/01.CIR.0000137826.09715.9C.

5. Semigolovskii N.Yu., Titkov Yu.S., Gaidenko G.V. New in intensive therapy of thromboembolism of small branches of the pulmonary artery. In: 4th Congress of Anesthesiologists and Resuscitators of Russia: theses of reports. Moscow; 1994, p. 267. (In Russ.)

6. Gaidenko G.V., Losev N.A., Semigolovskii N.Yu. Method for the treatment of pulmonary embolism. Patent RU 2224525 C1, 27.02.2004. (In Russ.) Available at: https://yandex.ru/patents/doc/RU2224525C1_20040227.

7. Semigolovskii N.Yu., Gaidenko G.V., Malashenko A.V. Pulmonary embolism: epidemiology, diagnosis, prospects for prevention and treatment. Herald of North-Western State Medical University named after I.I. Mechnikov. 2002;3(3):16–18. (In Russ.)

8. Fralick M., Colacci M., Schneeweiss S., Huybrechts K.F., Lin K.J., Gagne J.J. Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study. Ann Intern Med. 2020;172(7):463–473. https://doi.org/10.7326/M19-2522.

9. Cohen A.T., Hamilton M., Bird A., Mitchell S.A., Li S., Horblyuk R., Batson S. Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis. PLoS ONE. 2016;11(8):e0160064. https://doi.org/10.1371/journal.pone.0160064.

10. Semigolovskii N.Yu., Gaidenko G.V. Ultrasound inhalations of heparin in acute coronary syndrome and pulmonary embolism. In: Fundamental science and clinical medicine: collection of scientific reports of the conference, St Petersburg, November 15–16, 2007. St Petersburg; 2007, pp. 101–102. (In Russ.)

11. Semigolovskii N.Yu., Azanov B.A., Vertsinsky E.K., Ivanova E.V., Gaidenko G.V. Advantages of ultrasonic heparin inhalations. Arterial Hypertension (Russian Federation). 2008;14(1S-1):24. (In Russ.)

12. Semigolovskii N.Yu., Gaidenko G.V., Kozlov K.L., Malashenko A.V. Heparin inhalation for the prevention of pulmonary embolism in the postoperative period. In: Man and Medicine: Abstracts of the 9th Russian National Congress, Moscow, April 8–12, 2002. Moscow; 2002, p. 95. (In Russ.)

13. Semigolovskii N.Yu., Azanov B.A., Vertsinsky E.K., Ivanova E.V., Gaidenko G.V. Ultrasonic inhalation of heparin as a modern method of prevention of thromboembolic complications. In: Proceedings of a scientific conference with international participation dedicated to the 200th anniversary of the birth of N.I. Pirogov, St Petersburg, November 25–27, 2010. St Petersburg: Military Medical Academy named after S. M. Kirov; 2010, p. 364. (In Russ.)

14. Dixon B., Schultz M.J., Smith R., Fink J.B., Santamaria J.D., Campbell D.J. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial. Crit Care. 2010;14(5):R180. https://doi.org/10.1186/cc9286.

15. Bandeshe H., Boots R., Dulhunty J., Dunlop R., Holley A., Jarrett P. et al. Is inhaled prophylactic heparin useful for prevention and Management of Pneumonia in ventilated ICU patients?: The IPHIVAP investigators of the Australian and New Zealand Intensive Care Society Clinical Trials Group. J Crit Care. 2016;34:95–102. https://doi.org/10.1016/j.jcrc.2016.04.005.

16. Dixon B., Smith R., Santamaria J.D., Orford N.R., Wakefield B.J., Ives K. et al. A trial of nebulised heparin to limit lung injury following cardiac surgery. Anaesth Intensive Care. 2016;44(1):28–33. https://doi.org/10.1177/0310057X1604400106.

17. Dixon B., Schultz M.J., Hofstra J.J., Campbell D.J., Santamaria J.D. Nebulized heparin reduces levels of pulmonary coagulation activation in acute lung injury. Crit Care. 2010;14(5):445. https://doi.org/10.1186/cc9269.

18. Bendstrup K.E., Gram J., Jensen J.I. Effect of inhaled heparin on lung function and coagulation in healthy volunteers. Eur Respir J. 2002;19(4):606–610. https://doi.org/10.1183/09031936.02.00105202.

19. Phelps M.K., Olson L.M., Patel M.A.V.B., Thompson M.J., Murphy C.V. Nebulized Heparin for Adult Patients With Smoke Inhalation Injury: A Review of the Literature. J Pharm Technol. 2020;36(4):130–140. https://doi.org/10.1177/8755122520925774.

20. Juschten J., Tuinman P.R., Juffermans N.P., Dixon B., Levi M., Schultz M.J. Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies. Ann Transl Med. 2017;5(22):444. https://doi.org/10.21037/atm.2017.08.23.

21. Yildiz-Pekoz A., Ozsoy Y. Inhaled Heparin: Therapeutic Efficacy and Recent Formulations. J Aerosol Med Pulm Drug Deliv. 2017;30(3):143–156. https://doi.org/10.1089/jamp.2015.1273.

22. Van Haren F.M.P., Page C., Laffey J.G., Artigas A., Camprubi-Rimblas M., Nunes Q. et al. Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence. Crit Care. 2020;24(1):454. https://doi.org/10.1186/s13054-020-03148-2.

23. Van Haren F.M.P., Laffey J.G., Artigas A., Page C., Schultz M.J., Cosgrave D. et al. Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation MetaTrial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies. Br J Clin Pharmacol. 2022;88(7):3272–3287. https://doi.org/10.1111/bcp.15253.

24. Bertanha M., Rodrigues L.D.S., Mellucci Filho P.L., Moroz A., Pardini M.I.M.C., Sobreira M.L. et al. Nebulized enriched heparin to treat no critical patients with Sars-Cov-2: Triple-blind clinical trial. Medicine (Baltimore). 2021;100(51):e28288. https://doi.org/10.1097/MD.0000000000028288.