medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2022-16-4-82-88medsovet-6772Research ArticleCOVID-19Аторвастатин: старый знакомый в свете пандемии новой коронавирусной инфекцииAtorvastatin: old friend in the light of novel coronavirus infection’s pandemiahttps://orcid.org/0000-0002-1518-6552ЕжовМ. В.EzhovM. V.

Ежов Марат Владиславович, д.м.н., профессор, главный научный сотрудник лаборатории нарушений липидного обмена

121552, Москва, 3-я Черепковская ул., д. 15а

Marat V. Ezhov, Dr. Sci. (Med.), Professor, Chief Researcher, Laboratory of Lipid Metabolism Disorders

15a, 3rd Cherepkovskaya St., Moscow,121552

marat_ezhov@mail.ruhttps://orcid.org/0000-0002-0316-2940КолмаковаТ. Е.KolmakovaT. E.

Колмакова Татьяна Евгеньевна, к.м.н., научный сотрудник лаборатории нарушений липидного обмена

121552, Москва, 3-я Черепковская ул., д. 15а

Tatyana E. Kolmakova, Cand. Sci. (Med.), Researcher, Laboratory of Lipid Metabolism Disorders

15a, 3rd Cherepkovskaya St., Moscow,121552

kolmakova70@mail.ruhttps://orcid.org/0000-0001-5977-1457МатвееваМ. А.MatveevaM. M.

Матвеева Марина Александровна, младший научный сотрудник отдела проблем атеросклероза

121552, Москва, 3-я Черепковская ул., д. 15а

Marina A. Matveeva, Junior Researcher, Department of Problems of Atherosclerosis

15a, 3rd Cherepkovskaya St., Moscow,121552

marmat13@inbox.ruhttps://orcid.org/0000-0001-9685-4569АлексееваИ. А.AlekseevaI. A.

Алексеева Ирина Александровна, к.м.н., научный сотрудник лаборатории нарушений липидного обмена

121552, Москва, 3-я Черепковская ул., д. 15а

Irina A. Alekseeva, Cand. Sci. (Med.), Researcher, Laboratory of Lipid Metabolism Disorders

15a, 3rd Cherepkovskaya St., Moscow,121552

iralex66@mail.ruНаучно-исследовательский институт клинической кардиологии имени А.Л. Мясникова Национального медицинского исследовательского центра кардиологииРоссияMyasnikov Research Institute of Clinical Cardiology, National Medical Research Center of CardiologyRussian Federation202206042022048288Copyright © Ежов М.В., Колмакова Т.Е., Матвеева М.А., Алексеева И.А., 20222022Ежов М.В., Колмакова Т.Е., Матвеева М.А., Алексеева И.А.Ezhov M.V., Kolmakova T.E., Matveeva M.M., Alekseeva I.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/6772

Пандемия COVID-19 (COronaVIrus Disease 2019), вызванная коронавирусом SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2), продолжает являться глобальным бременем для населения и систем здравоохранения. На 21 марта 2022 г. в мире насчитывается более 460 млн случаев заболевания и более 6 млн смертей, а в Российской Федерации – более 17 млн и 360 тыс. соответственно. В связи с быстрым распространением новой коронавирусной инфекции с начала пандемии огромные усилия прилагаются для создания новых фармакологических средств для уменьшения заболеваемости и  смертности, а  также применяется тактика перепрофилирования существующих лекарственных препаратов в  схемах лечения пациентов с COVID-19, в частности, статинов. Статины представляют собой один из наиболее широко используемых и назначаемых в мире классов препаратов. Гиполипидемические свойства статинов активно используются для лечения гиперлипидемии и  первичной и  вторичной профилактики сердечно-сосудистых заболеваний и  их осложнений. Статины обладают известным профилем безопасности, недороги и  доступны. Помимо гиполипидемического эффекта, статины обладают широким спектром плейотропных противовоспалительных, противовирусных, антитромботических эффектов, потенциально полезных в  лечении COVID-19. Предположительно, использование статинов может уменьшить обусловленное SARS-CoV-2 повреждение органов и тканей, улучшить функцию легких. Применение статинов, в частности, аторвастатина, как одного из  наиболее эффективных, широко назначаемых и  изученных препаратов данного класса, в качестве безопасной, доступной и относительно недорогой терапии может быть перспективным терапевтическим подходом в борьбе против новой коронавирусной инфекции.

The COVID-19 (COronaVIrus Disease 2019) pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2) continues to be a global threat to people and health systems. As of March 21, 2022, there are more than 460 million cases and more than 6 million deaths worldwide, and more than 17 million and 360,000 respectively in the Russian Federation. Due to the rapid spread of the new coronavirus infection, since the beginning of the pandemic, tremendous efforts have been made to create new pharmacological agents to reduce morbidity and mortality, and tactics have been used to repurpose existing medications in treatment regimens for patients with COVID-19, particularly statins. Statins represent one of the most widely used and prescribed classes of drugs in the world. The hypolipidemic properties of statins are actively used to treat hyperlipidemia and primary and secondary prevention of cardiovascular diseases and their complications. Statins have a known safety profile, are inexpensive and accessible. In addition to their hypolipidemic effects, statins have a wide range of pleiotropic anti-inflammatory, antiviral, and antithrombotic effects potentially useful in the treatment of COVID-19. Presumably, the use of statins can reduce SARS-CoV-2-induced organ and tissue damage and improve lung function. The use of statins, particularly atorvastatin, as one of the most effective, widely prescribed and studied drugs in this class, as a safe, affordable and relatively inexpensive therapy may be a promising therapeutic approach in the fight against a new coronavirus infection.

статиныплейотропные свойствадисфункция эндотелияпереориентацияCOVID-19statinspleiotropic effectrepurposingendothelial dysfunctionCOVID-19ReferencesGrasselli G., Zangrillo A., Zanella A., Antonelli M., Cabrini L., Castelli A. et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574–1581. https://doi.org/10.1001/jama.2020.5394.Grasselli G., Zangrillo A., Zanella A., Antonelli M., Cabrini L., Castelli A. et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574–1581. https://doi.org/10.1001/jama.2020.5394.Wang Y., Foo R., Thum T. Using “old” medications to fight new COVID-19: Re-purposing with a purpose. J Mol Cell Cardiol. 2020;146:41–42. https://doi.org/10.1016/j.yjmcc.2020.07.005.Wang Y., Foo R., Thum T. Using “old” medications to fight new COVID-19: Re-purposing with a purpose. J Mol Cell Cardiol. 2020;146:41–42. https://doi.org/10.1016/j.yjmcc.2020.07.005.Авдеев С.Н., Адамян Л.В., Алексеева Е.И., Багненко С.Ф., Баранов А.А., Белевский А.С. и др. Временные методические рекомендации: профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19). М.; 2021. 224 с. Режим доступа: http://nasci.ru/?id=40123&download=1.Avdeev S.N., Adamyan L.V., Alekseeva E.I., Bagnenko S.F., Baranov A.A., Belevskiy A.S. et al. Interim guidelines: prevention, diagnosis and treatment of a new coronavirus infection (COVID-19). Moscow; 2021. 224 p. (In Russ.) Available at: http://nasci.ru/?id=40123&download=1.Mach F., Baigent C., Catapano A.L, Koskinas K.C., Casula M., Badimon L. et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–188. https://doi.org/10.1093/eurheartj/ehz455.Mach F., Baigent C., Catapano A.L, Koskinas K.C., Casula M., Badimon L. et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–188. https://doi.org/10.1093/eurheartj/ehz455.Кухарчук В.В., Ежов М.В., Сергиенко И.В., Арабидзе Г.Г., Бубнова М.Г. и др. Диагностика и коррекция нарушений липидного обмена с целью профилактики и лечения атеросклероза. Российские рекомендации, VII пересмотр. Атеросклероз и дислипидемии. 2020;(1(38):7–42. Режим доступа: https://jad.noatero.ru/index.php/jad/article/view/274/.Kukharchuk V.V., Ezhov M.V., Sergienko I.V., Arabidze G.G., Bubnova M.G., Balakhonova T.V. et al. Diagnostics and correction of lipid metabolism disorders in order to prevent and treat of atherosclerosis Russian recommendations VII revision. Moscow, 2020. The Journal of Atherosclerosis and Dyslipidemias. 2020;1(38):7–42. (In Russ.) Available at: https://jad.noatero. ru/index.php/jad/article/view/274/.Bifulco M., Endo A. Statin: new life for an old drug. Pharmacol. Res. 2014;88:1–2. https://doi.org/10.1016/j.phrs.2014.06.005.Bifulco M., Endo A. Statin: new life for an old drug. Pharmacol. Res. 2014;88:1–2. https://doi.org/10.1016/j.phrs.2014.06.005.Bifulco M., Gazzerro P. Statins in coronavirus outbreak: It’s time for experimental and clinical studies. Pharmacol Res. 2020;156:104803. https://doi.org/10.1016/j.phrs.2020.104803.Bifulco M., Gazzerro P. Statins in coronavirus outbreak: It’s time for experimental and clinical studies. Pharmacol Res. 2020;156:104803. https://doi. org/10.1016/j.phrs.2020.104803.Zhang X.J., Qin J.J., Cheng X., Shen L., Zhao Y.C, Yuan Y. et al. In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020;32(2):176–187.e4. https://doi.org/10.1016/j.cmet.2020.06.015.Zhang X.J., Qin J.J., Cheng X., Shen L., Zhao Y.C, Yuan Y. et al. In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metab. 2020;32(2):176–187.e4. https://doi. org/10.1016/j.cmet.2020.06.015.Vitiello A., Ferrara F. Plausible Positive Effects of Statins in COVID-19 Patient. Cardiovasc Toxicol. 2021;21(10):781–789. https://doi.org/10.1007/s12012-021-09674-x.Vitiello A., Ferrara F. Plausible Positive Effects of Statins in COVID-19 Patient. Cardiovasc Toxicol. 2021;21(10):781–789. https://doi.org/10.1007/ s12012-021-09674-x.Orlowski S., Mourad J.J., Gallo A., Bruckert E. Coronaviruses, cholesterol and statins: Involvement and application for Covid-19. Biochimie. 2021;189:51–64. https://doi.org/10.1016/j.biochi.2021.06.005.Orlowski S., Mourad J.J., Gallo A., Bruckert E. Coronaviruses, cholesterol and statins: Involvement and application for Covid-19. Biochimie. 2021;189:51–64. https://doi.org/10.1016/j.biochi.2021.06.005.Gorabi A.M., Kiaie N., Bianconi V., Jamialahmadi T., Al-Rasadi K., Johnston T.P. et al. Antiviral effects of statins. Prog Lipid Res. 2020;79:101054. https://doi.org/10.1016/j.plipres.2020.101054.Gorabi A.M., Kiaie N., Bianconi V., Jamialahmadi T., Al-Rasadi K., Johnston T.P. et al. Antiviral effects of statins. Prog Lipid Res. 2020;79:101054. https://doi. org/10.1016/j.plipres.2020.101054.Reiner Ž., Hatamipour M., Banach M., Pirro M., Al-Rasadi K., Jamialahmadi T. et al. Statins and the COVID-19 main protease: in silico evidence on direct interaction. Arch Med Sci. 2020;16(3):490–496. https://doi.org/10.5114/ aoms.2020.94655.Reiner Ž., Hatamipour M., Banach M., Pirro M., Al-Rasadi K., Jamialahmadi T. et al. Statins and the COVID-19 main protease: in silico evidence on direct interaction. Arch Med Sci. 2020;16(3):490–496. https://doi.org/10.5114/ aoms.2020.94655.Ежов М.В., Попова М.Д., Алексеева И.А., Покровский Н.С., Палеев Ф.Н. Новая коронавирусная инфекция: от патогенеза к терапии. Кардиологический вестник. 2021;16(1):10–19. https://doi.org/10.17116/Cardiobulletin20211601110.Ezhov M.V., Popova M.D., Alekseeva I.A., Pokrovsky N.S., Paleev F.N. Novel coronavirus infection: from pathogenesis to therapy. Russian Cardiology Bulletin. 2021;16(1):10–19. (In Russ.) https://doi.org/10.17116/ Cardiobulletin20211601110.Evans P.C., Rainger G.E., Mason J.C., Guzik T.J., Osto E., Stamataki Z. et al. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res. 2020;116(14):2177–2184. https://doi.org/10.1093/cvr/cvaa230.Evans P.C., Rainger G.E., Mason J.C., Guzik T.J., Osto E., Stamataki Z. et al. Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science. Cardiovasc Res. 2020;116(14):2177–2184. https://doi.org/10.1093/cvr/cvaa230.Nägele M.P., Haubner B., Tanner F.C., Ruschitzka F., Flammer A.J. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis. 2020;314:58–62. https://doi.org/10.1016/j.atherosclerosis.2020.10.014.Nägele M.P., Haubner B., Tanner F.C., Ruschitzka F., Flammer A.J. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Atherosclerosis. 2020;314:58–62. https://doi.org/10.1016/j.atherosclerosis.2020.10.014.Yuan S. Statins May Decrease the Fatality Rate of Middle East Respiratory Syndrome Infection. mBio. 2015;6(4):e01120. https://doi.org/10.1128/mbio.01120-15.Yuan S. Statins May Decrease the Fatality Rate of Middle East Respiratory Syndrome Infection. mBio. 2015;6(4):e01120. https://doi.org/10.1128/ mbio.01120-15.Rizk J.G., Kalantar-Zadeh K., Mehra M.R., Lavie C.J., Rizk Y., Forthal D.N. Pharmaco-Immunomodulatory Therapy in COVID-19. Drugs. 2020;80(13):1267–1292. https://doi.org/10.1007/s40265-020-01367-z.Rizk J.G., Kalantar-Zadeh K., Mehra M.R., Lavie C.J., Rizk Y., Forthal D.N. Pharmaco-Immunomodulatory Therapy in COVID-19. Drugs. 2020;80(13):1267–1292. https://doi.org/10.1007/s40265-020-01367-z.Lohia P., Kapur S., Benjaram S., Cantor Z., Mahabadi N., Mir T., Badr M.S. Statins and clinical outcomes in hospitalized COVID-19 patients with and without Diabetes Mellitus: a retrospective cohort study with propensity score matching. Cardiovasc Diabetol. 2021;20(1):140. https://doi.org/10.1186/s12933-021-01336-0.Lohia P., Kapur S., Benjaram S., Cantor Z., Mahabadi N., Mir T., Badr M.S. Statins and clinical outcomes in hospitalized COVID-19 patients with and without Diabetes Mellitus: a retrospective cohort study with propensity score matching. Cardiovasc Diabetol. 2021;20(1):140. https://doi.org/10.1186/ s12933-021-01336-0.Marić I., Oskotsky T., Kosti I., Le B., Wong R.J., Shaw G.M. et al. Decreased Mortality Rate Among COVID-19 Patients Prescribed Statins: Data From Electronic Health Records in the US. Front Med (Lausanne). 2021;8:639804. https://doi.org/10.3389/fmed.2021.639804.Marić I., Oskotsky T., Kosti I., Le B., Wong R.J., Shaw G.M. et al. Decreased Mortality Rate Among COVID-19 Patients Prescribed Statins: Data From Electronic Health Records in the US. Front Med (Lausanne). 2021;8:639804. https://doi.org/10.3389/fmed.2021.639804.Hariyanto H.I., Kurniawan A. Statin therapy did not improve the in-hospital outcome of coronavirus disease 2019 (COVID-19) infection. Diabetes Metab Syndr. 2020;14(6):1613–1615. https://doi.org/10.1016/j.dsx.2020.08.023.Hariyanto H.I., Kurniawan A. Statin therapy did not improve the in-hospital outcome of coronavirus disease 2019 (COVID-19) infection. Diabetes Metab Syndr. 2020;14(6):1613–1615. https://doi.org/10.1016/j.dsx.2020.08.023.Diaz-Arocutipa C., Melgar-Talavera B., Alvarado-Yarasca Á., SaraviaBartra M.M., Cazorla P., Belzusarri I., Hernandez A.V. Statins reduce mortality in patients with COVID-19: an updated meta-analysis of 147 824 patients. Int J Infect Dis. 2021;110:374–381. https://doi.org/10.1016/j.ijid.2021.08.004.Diaz-Arocutipa C., Melgar-Talavera B., Alvarado-Yarasca Á., SaraviaBartra M.M., Cazorla P., Belzusarri I., Hernandez A.V. Statins reduce mortality in patients with COVID-19: an updated meta-analysis of 147 824 patients. Int J Infect Dis. 2021;110:374–381. https://doi.org/10.1016/j.ijid.2021.08.004.Алексеева И.А., Сергиенко И.В. Роль аторвастатина во вторичной профилактике сердечно-сосудистых заболеваний в свете современных рекомендаций. Атеросклероз и дислипидемии. 2017;3(28):23–32. Режим доступа: https://elibrary.ru/item.asp?id=29667696.Alekseeva I.A., Sergienko I.V. Atorvastatin in secondary prevention of cardiovascular diseases in the light of modern recommendations. The Journal of Atherosclerosis and Dyslipidemias. 2017;3(28):23–32. (In Russ.) Available at: https://elibrary.ru/item.asp?id=29667696.Gupta A., Madhavan M.V., Sehgal K., Nair N., Mahajan S., Sehrawat T.S. et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017–1032. https://doi.org/10.1038/s41591-020-0968-3.Gupta A., Madhavan M.V., Sehgal K., Nair N., Mahajan S., Sehrawat T.S. et al. Extrapulmonary manifestations of COVID-19. Nat Med. 2020;26(7):1017–1032. https://doi.org/10.1038/s41591-020-0968-3.Kumar V., Liu H., Wu C. Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations. Comput Biol Med. 2021;135:104634. https://doi.org/10.1016/j.compbiomed.2021.104634.Kumar V., Liu H., Wu C. Drug repurposing against SARS-CoV-2 receptor binding domain using ensemble-based virtual screening and molecular dynamics simulations. Comput Biol Med. 2021;135:104634. https://doi. org/10.1016/j.compbiomed.2021.104634.Xu S., Liu Y., Ding Y., Luo S., Zheng X., Wu X. et al. The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction. Signal Transduct Target Ther. 2021;6(1):266. https://doi.org/10.1038/s41392-021-00690-5.Xu S., Liu Y., Ding Y., Luo S., Zheng X., Wu X. et al. The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction. Signal Transduct Target Ther. 2021;6(1):266. https://doi.org/10.1038/ s41392-021-00690-5.Castiglione V., Chiriacò M., Emdin M., Taddei S., Vergaro G. Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020;6(4):258–259. https://doi.org/10.1093/ehjcvp/pvaa042.Castiglione V., Chiriacò M., Emdin M., Taddei S., Vergaro G. Statin therapy in COVID-19 infection. Eur Heart J Cardiovasc Pharmacother. 2020;6(4):258–259. https://doi.org/10.1093/ehjcvp/pvaa042.Haji Aghajani M., Moradi O., Azhdari Tehrani H., Amini H., Pourheidar E., Hatami F. et al. Promising effects of atorvastatin on mortality and need for mechanical ventilation in patients with severe COVID-19; a retrospective cohort study. Int J Clin Pract. 2021;75(9):e14434. https://doi.org/10.1111/ijcp.14434.Haji Aghajani M., Moradi O., Azhdari Tehrani H., Amini H., Pourheidar E., Hatami F. et al. Promising effects of atorvastatin on mortality and need for mechanical ventilation in patients with severe COVID-19; a retrospective cohort study. Int J Clin Pract. 2021;75(9):e14434. https://doi.org/10.1111/ ijcp.14434.Vahedian-Azimi A., Rahimibashar F., Najafi A., Kidde J., Shahriary A., Shojaei S. et al. Associastion of In-hospital Use of Statins, Aspirin, and Renin-Angiotensin-Aldosterone Inhibitors with Mortality and ICU Admission Due to COVID-19. Adv Exp Med Biol. 2021;1327:205–214. https://doi.org/10.1007/978-3-030-71697-4_17.Vahedian-Azimi A., Rahimibashar F., Najafi A., Kidde J., Shahriary A., Shojaei S. et al. Associastion of In-hospital Use of Statins, Aspirin, and Renin-Angiotensin-Aldosterone Inhibitors with Mortality and ICU Admission Due to COVID-19. Adv Exp Med Biol. 2021;1327:205–214. https://doi. org/10.1007/978-3-030-71697-4_17.Rodriguez-Nava G., Trelles-Garcia D.P., Yanez-Bello M.A., Chung C.W., TrellesGarcia V.P., Friedman H.J. Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study. Crit Care. 2020;24(1):429. https://doi.org/10.1186/s13054-020-03154-4.Rodriguez-Nava G., Trelles-Garcia D.P., Yanez-Bello M.A., Chung C.W., TrellesGarcia V.P., Friedman H.J. Atorvastatin associated with decreased hazard for death in COVID-19 patients admitted to an ICU: a retrospective cohort study. Crit Care. 2020;24(1):429. https://doi.org/10.1186/s13054-020-03154-4.Sharma A., Sharma C., RainaS., Singh B., Dadhwal D.S., Dogra V. et al. A randomized open-label trial to evaluate the efficacy and safety of triple therapy with aspirin, atorvastatin, and nicorandil in hospitalised patients with SARS-CoV-2 infection: A structured summary of a study protocol for a randomized controlled trial. Trials. 2021;22(1):451. https://doi.org/10.1186/s13063-021-05361-y.Sharma A., Sharma C., RainaS., Singh B., Dadhwal D.S., Dogra V. et al. A randomized open-label trial to evaluate the efficacy and safety of triple therapy with aspirin, atorvastatin, and nicorandil in hospitalised patients with SARS-CoV-2 infection: A structured summary of a study protocol for a randomized controlled trial. Trials. 2021;22(1):451. https://doi.org/10.1186/s13063-021-05361-y.Ghati N.,Roy A.,Bhatnagar S., Bhati S.,Bhushan S., Mahendran M. et al. Atorvastatin and Aspirin as Adjuvant Therapy in Patients with SARS-CoV-2 Infection: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):902. https://doi.org/10.1186/s13063-020-04840-y.Ghati N.,Roy A.,Bhatnagar S., Bhati S.,Bhushan S., Mahendran M. et al. Atorvastatin and Aspirin as Adjuvant Therapy in Patients with SARS-CoV-2 Infection: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):902. https://doi.org/10.1186/s13063-020-04840-y.

The authors declare that there are no conflicts of interest present.