Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC MVnrpLKzrkghgvzckb9YXSp 00147 S0066-782X2021000100147 abc.20200949 10.36660/abc.20200949 Carta Científica Estatinas e COVID-19: Suspender ou não Suspender? Eis a Questão! 0000-0001-6929-8392 Ferrari Filipe 1 Santos Raul D. 2 3 Programa de Pós-Graduação em Cardiologia e Ciências Cardiovasculares Universidade Federal do Rio Grande do Sul Hospital de Clínicas de Porto Alegre Porto Alegre RS Brasil Programa de Pós-Graduação em Cardiologia e Ciências Cardiovasculares, Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS - Brasil Instituto do Coração Faculdade de Medicina Universidade de São Paulo São Paulo SP Brasil Unidade Clínica de Lípides, Instituto do Coração (InCor), Hospital da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP - Brasil Hospital Israelita Albert Einstein São Paulo SP Brasil Hospital Israelita Albert Einstein, São Paulo, SP – Brasil Correspondência: Raul D. Santos • Av. Albert Einstein, 627. CEP 05652-900, São Paulo, SP - Brasil E-mail: rauldsf@gmail.com

Contribuição dos Autores

Concepção e desenho da pesquisa, Obtenção de dados, Análise e interpretação dos dados e Redação do manuscrito: Ferrari F, Santos RD; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Santos RD.

Potencial Conflito de Interesses

RDS recebeu honorários relacionados a atividades de consultoria, pesquisa e/ou palestras de: Aché, Amgen, AstraZeneca, Esperion, Kowa, Novo Nordisk, Merck, MSD, Pfizer, PTC e Sanofi/Regeneron. FF declara não haver conflitos de interesse.

 03 02 2021 01 2021 116 1 147 152 10 08 2020 28 09 2020 10 10 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. COVID-19 Coronavírus Betacoronavírus Pandemia Colesterol Dislipidemias Infecção Inibidores de Hidroximetilglutaril-CoA Redutases Lipoproteínas Coordenação de Aperfeiçoamento de Pessoal de Nível Superior 001 Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico 303734/2018-3 Fontes de Financiamento Introdução

Em meio a tantas incertezas que permeiam a nova doença de coronavírus 2019 (COVID-19), as evidências relacionando a presença de dislipidemia à gravidade da doença e às consequentes implicações prognósticas ainda são escassas. Em maio de 2020, um estudo chinês retrospectivo investigou a associação entre as mudanças nos níveis de colesterol e o prognóstico em aproximadamente 600 pacientes com COVID-19, pareados por idade e sexo com controles saudáveis. Primeiramente, observou-se que os níveis de colesterol de lipoproteína de baixa densidade (LDL-C) e colesterol total foram significativamente mais baixos em pacientes com COVID-19. Em segundo lugar, houve uma tendência para os níveis de LDL-C e de colesterol total diminuirem à medida que a gravidade da infecção aumentava (leve, grave e crítica, respectivamente).1 No mesmo estudo, os níveis de colesterol de lipoproteína de alta densidade (HDL-C) também diminuíram em casos graves. Foram observados dados parecidos por Fan et al.,2onde os níveis de LDL-C foram inversamente associados à gravidade da COVID-19. Esses dados sugeriram uma possível relação entre níveis baixos de colesterol e piora da infecção por COVID-19. Além disso, estudos experimentais têm mostrado que as estatinas podem aumentar a abundância da enzima conversora de angiotensina 2 (ECA2), o que pode contribuir parcialmente para a entrada do vírus na célula e o aumento do risco de infectividade.3

Com base nesses achados prévios, foi hipotetizado que o uso de terapias hipolipemiantes como as estatinas poderiam agravar a infecção por COVID-19. No entanto, sabe-se que os níveis de colesterol sérico podem cair em pacientes com infecções virais ou bacterianas ativas,4,5 uma vez que o LDL e o HDL desempenham um papel no sistema imunológico.6 Por outro lado, a hiperlipidemia pode comprometer a resposta imunológica e agravar ainda mais o estado inflamatório dos pacientes com COVID-19, aumentando o risco cardiovascular.7Desta maneira, surge a seguinte pergunta: as estatinas deveriam ou não ser suspensas em pacientes com COVID-19?

COVID-19, Infecções, Trombose e Estatinas Evidências de Benefícios Potenciais

Além de diminuir as lipoproteínas pró-aterogênicas, as estatinas apresentam outros efeitos sistêmicos bem documentados, como a melhora da disfunção endotelial e as propriedades anti-inflamatórias e anti-trombóticas que levam à estabilização das placas ateroscleróticas.8Meta-análises de ensaios clínicos randomizados mostraram que as estatinas podem reduzir significativamente as concentrações de proteína C reativa,9 antígeno do fator de von Willebrand10 e endotelina-1.11

Um estudo observacional com 3.043 pacientes hospitalizados pelo vírus influenza encontrou menor risco de mortalidade naqueles que estavam em uso de estatinas, antes ou durante a hospitalização (odds ratio [OR] ajustado 0,59).12Também foi observado um benefício das estatinas em pacientes hospitalizados com pneumonia viral, resultando em menor mortalidade e necessidade de intubação (OR 0,26).13

Dado o estado pró-inflamatório e pró-trombótico observado em pacientes com COVID-19 mais grave, as características dessas drogas podem ser importantes para esses pacientes.

A Tabela 1 mostra detalhes de alguns estudos que examinaram os efeitos das estatinas em pacientes com infecções virais e COVID-19.

– Evidências de possíveis benefícios das estatinas no cenário de doenças virais, bem como na COVID-19
Estudo Desenho do Estudo Pacientes e Doença Total (N) Idade média Ajuste para covariáveis Resultados
Vandermeer et al. 201112 Multiestado Pacientes hospitalizados com infecções pelo vírus influenza 3.043 70 anos Idade, raça, DCV, doença pulmonar e renal, vacinação contra influenza e administração de medicamentos antivirais

Estatinas antes ou durante a hospitalização versus nenhuma estatina foram associadas a chances de proteção contra a mortalidade em 30 dias

OR ajustado 0,59; IC 95%, 0,30 a 0,92
Henry et al. 201813 Retrospectivo Pacientes com pneumonia viral 539 64 anos NA

Estatinas continuadas no hospital versus descontinuação reduziram mortes e/ou necessidade de intubação durante a internação hospitalar

OR 0,26; IC 95%, 0,08 a 0,81; p = 0,02
De Spiegeleer et al. 202014 Coorte multicêntrica retrospectiva Sujeitos positivos para COVID-19 154 86 anos Idade, sexo, estado funcional, hipertensão e diabetes mellitus

O uso de estatinas foi relacionado à ausência de sintomas durante COVID-19

OR 2,91; IC 95%, 1,27 a 6,71; p = 0,011

OR ajustado 2,65; IC 95%, 1,13 a 6,68; p = 0,028
Zhang et al. 202015 Retrospectivo Pacientes hospitalizados por COVID-19 13.981 58 anos Idade, sexo e SpO2 no momento da admissão

Uso de estatinas versus nenhuma estatina foi correlacionado à redução no risco de mortalidade por todas as causas em 28 dias

HR ajustado 0,58; IC 95%, 0,43 a 0,80; p = 0,001
Rodriguez-Nava et al. 202016 Coorte retrospectiva Pacientes com COVID-19 admitidos à unidade de terapia intensiva 87 68 anos Idade, hipertensão, DCV, ventilação mecânica invasiva, frequência respiratória > 30, SpO2 < 94%, PaO2 / FiO2 < 300 mmHg ou infiltrados pulmonares > 50%, número de comorbidades e outras terapias adjuvantes (incluindo hidroxicloroquina, esteróides intravenosos, azitromicina, tocilizumabe, colchicina e antibióticos)

O uso de estatina (especificamente atorvastatina) reduziu a progressão à morte

HR ajustado 0,38, IC 95%, 0,18 a 0,77; p = 0,008
Daniels et al. 202017 Unicêntrico retrospectivo Pacientes hospitalizados por COVID-19 170 59 anos Idade, sexo, obesidade, hipertensão, diabetes, doença renal crônica e DCV

Uso de estatinas antes da admissão reduziu o desenvolvimento de doença grave

OR ajustado 0,29; IC 95%, 0,11 a 0,71; p = 0,009

O uso de estatinas aumentou a taxa de recuperação da COVID-19 entre os indivíduos que ainda não haviam experimentado doença grave

HR ajustado por causa específica para recuperação 2,69; IC 95%, 1,36 a 5,33; p = 0,004
Song et al. 202018 Coorte retrospectiva Pacientes hospitalizados por COVID-19 249 62 anos Idade, sexo, raça, DCV, doença pulmonar crônica, diabetes e obesidade

O uso de estatinas diminuiu o risco de ventilação mecânica invasiva

OR ajustado 0,45; IC 95%, 0,20 a 0,99; p = 0,048

OR: odds ratio; HR: hazard ratio; IC: intervalo de confiança; SpO2: saturação periférica de oxigênio: DCV: doença cardiovascular; NA: não aplicável.

Em um estudo de coorte retrospectivo da Bélgica, De Spiegeleer et al.14 avaliaram 154 pessoas idosas (idade média: 86 anos) que contraíram COVID-19, observando uma tendência significativa para ausência de sintomas naqueles que recebiam estatinas anteriormente (OR 2,91; intervalo de confiança (IC) 95%, 1,27 a 6,71). Isto permaneceu estatisticamente significativo mesmo após o ajuste para covariáveis (OR 2,65; IC 95%, 1,13 a 6,68).

Outro estudo retrospectivo de aproximadamente 14.000 pacientes com COVID-19 encontrou menor risco de mortalidade com o uso prévio de estatinas. Neste estudo, 1.219 pacientes estavam recebendo estatinas e a mortalidade geral em 28 dias neste grupo foi de 5,2%, enquanto no grupo sem estatinas foi de 9,4% (hazard ratio [HR] ajustado 0,58; IC 95%, 0,43 a 0,80; p = 0,001).15 Em outro estudo com 87 pacientes com COVID-19 internados na unidade de terapia intensiva, uma progressão mais lenta para a morte foi encontrada naqueles que receberam atorvastatina.16

Daniels et al.,17 por meio de um estudo retrospectivo de centro único, encontraram um risco reduzido de COVID-19 grave em pacientes que estavam recebendo estatinas antes da admissão (OR ajustado 0,29) e um tempo mais rápido de recuperação entre aqueles sem doença grave (HR ajustado para recuperação 2,69). Além disso, em um estudo de coorte retrospectivo de pacientes hospitalizados com COVID-19 (N = 249) nos Estados Unidos, o uso de estatinas foi correlacionado à diminuição do risco de ventilação mecânica invasiva (OR ajustado 0,45).18

Certamente, os estudos citados são severamente limitados por seu desenho retrospectivo; esses dados, apesar de favoráveis ao uso de estatinas em infecções virais, são apenas geradores de hipóteses, podendo estar sujeitos a um viés de seleção de indivíduos que recebem melhores cuidados. A questão que se segue é: há alguma evidência de que as estatinas possam prevenir doenças infecciosas? Em uma análise post hoc de pacientes incluídos no ensaio JUPITER,19que randomizou 17.802 indivíduos com LDL-C < 130 mg/dL e proteína C reativa de alta sensibilidade ≥ 2,0 mg/L para receber rosuvastatina 20 mg/dia ou placebo, seguidos por tempo mediano de 1,9 anos, Novack et al.20 observaram que o uso de estatinas reduziu, embora modestamente, a incidência de pneumonia (HR 0,83, IC 95%, 0,69 a 1,00). Esses resultados, que merecem ser comprovados em um ensaio adequadamente delineado, sugerem que as estatinas possam reduzir o risco de pneumonia devido a possíveis efeitos benéficos leves anti-inflamatórios, antioxidantes, imunomoduladores, anti-apoptóticos e endoteliais, segundo os autores.18É incerto se isso beneficiaria pacientes com COVID-19.

Além das complicações pulmonares, o SARS-CoV-2 também pode induzir a trombose.21 As estatinas teriam efeitos benéficos nestes casos? Em uma análise pré-especificada do mesmo ensaio JUPITER,19 foi analisado o impacto da rosuvastatina na primeira ocorrência de embolia pulmonar ou de tromboembolismo venoso. Embora não tenha havido diferenças nas taxas de embolia pulmonar entre os grupos (rosuvastatina e placebo), o grupo que recebeu a estatina apresentou uma redução de 43% nas taxas de tromboembolismo venoso (HR 0,57; IC 95%, 0,37 a 0,86; p = 0,007).22 Além disso, uma metanálise de 13 estudos de coorte observacionais (N = 3.148.259) e 23 ensaios clínicos randomizados (N = 118.464) mostrou que, tanto em estudos de coorte observacionais quanto em ensaios clínicos randomizados, houve uma redução no risco de trombose venosa profunda, mas não de embolia pulmonar, quando o uso de estatina foi comparado com os controles (risco relativo [RR] 0,75; IC 95%, 0,65 a 0,87; p < 0,0001; 0,85; IC 95%, 0,73 a 0,99; p = 0,038). Um benefício maior também foi encontrado para o risco de tromboembolismo venoso com o uso de rosuvastatina em comparação com outras estatinas (RR 0,57; IC 95%, 0,22 a 0,75; p = 0,015).23Possíveis mecanismos para explicar esses resultados incluem os efeitos das estatinas sobre fatores pró-trombóticos, como a redução do dímero D, fator VIII,24 inibidor do ativador do plasminogênio tipo 1 e níveis de fator tecidual, bem como a diminuição da agregação plaquetária e o aumento da expressão de trombomodulina.25A Figura 1 apresenta alguns mecanismos propostos onde as estatinas podem atuar como agentes anti-trombóticos e anti-inflamatórios e podem exercer efeitos favoráveis em pacientes com COVID-19.

– Alguns mecanismos propostos por meio dos quais as estatinas reduzem o estado pró-inflamatório e pro-trombótico em pacientes com COVID-19.<xref ref-type="bibr" rid="B8"><sup>8</sup></xref>-<xref ref-type="bibr" rid="B11"><sup>11</sup></xref>,<xref ref-type="bibr" rid="B24"><sup>24</sup></xref>,<xref ref-type="bibr" rid="B25"><sup>25</sup></xref> HMG-CoA redutase: 3-hidroxi-3-methyl-glutaril-CoA redutase; NF-κB: fator nuclear kappa B; VWF: fator de von Willebrand.

Visto que uma porção não negligenciável de pacientes infectados pelo SARS-CoV-2 (especialmente os pacientes mais graves) pode apresentar alterações no sistema de coagulação e uma alta taxa de tromboembolismo venoso,26 a manutenção das estatinas pode melhorar o prognóstico desses indivíduos. No entanto, da mesma forma que as possíveis propriedades anti-infecciosas, isso também precisa ser confirmado em ensaios clínicos randomizados.

 Suspensão de Estatinas e Aumento do Risco de Eventos Cardiovasculares?

A preocupação de que os níveis baixos de colesterol possam ser deletérios para pacientes com COVID-19 pode levar à suspensão inadequada de medicamentos hipolipemiantes em pacientes com alto risco de doença cardiovascular. As estatinas são a base fundamental para a terapia hipolipemiante com o objetivo de reduzir o risco de doença arterial coronariana (DAC); como grupo, as estatinas constituem um dos medicamentos mais prescritos no mundo. A metanálise do Cholesterol Treatment Trialists (CTT)27 mostrou que para cada redução de 1,0 mmol/L (~ 40 mg/dL) de LDL-C, houve uma redução de 10% na mortalidade por todas as causas (RR 0,90, IC 95%, 0,87 a 0,93; p < 0,0001), além de uma redução de 20% nas mortes por DAC (RR 0,80; IC 99%, 0,74 a 0,87; p < 0,0001).

Um cenário importante em que a suspensão de estatinas pode ser deletéria é durante o período inicial após um evento de síndrome coronariana aguda. Nesse cenário, a adição e manutenção de estatinas são fundamentais, e a suspensão do medicamento pode aumentar os riscos dos pacientes. Nesse sentido, um estudo observacional brasileiro com 249 pacientes observou um efeito inflamatório rebote na fase aguda do infarto do miocárdio (IM) após a retirada das estatinas. Sposito et al.28verificaram que, no começo do estudo, os pacientes que recebiam estatinas apresentavam valores de proteína C-reativa mais baixos quando comparados aos que não recebiam, antes do início do IM. No quinto dia após o IM, a mediana da proteína C reativa foi significativamente mais alta no grupo onde as estatinas foram suspensas.28 Em adição a isso, em uma análise de pacientes que apresentaram com DAC e dor no peito durante as últimas 24 horas no estudo PRISM29 (N = 1.616), Heeschen et al.30relataram que o uso de estatinas reduziu a taxa de eventos após 30 dias, em comparação com os pacientes sem esses medicamentos (HR ajustado 0,49, IC 95%, 0,21 a 0,86). Quando as estatinas foram suspensas após a admissão, o risco cardíaco aumentou (OR 2,93; IC 95%, 1,64 a 6,27; p = 0,005) e, embora não tenha sido estatisticamente significativo, houve uma tendência de maior risco em comparação com os pacientes que nunca receberam estatinas (OR 1,69; IC 95%, 0,92 a 3,56).29 Portanto, a retirada desses medicamentos deve ser vista com extrema cautela, principalmente após um evento coronariano agudo, pois pode levar ao surgimento de complicações, piorando o prognóstico dos pacientes.

Em suma, o uso de estatinas é baseado em uma literatura sólida e robusta, e a sua suspensão, exceto por indicação médica, pode levar a eventos agudos, aumentando ainda mais os riscos dos pacientes infectados por COVID-19, especialmente aqueles em prevenção secundária e aqueles que tiveram um evento coronário agudo recente. Os médicos e os pacientes devem manter esse conhecimento em mente.

 Quando Devemos Considerar a Suspensão das Estatinas em Pacientes com COVID-19?

De acordo com as diretrizes da Sociedade Europeia de Cardiologia, em casos raros em que os pacientes com COVID-19 desenvolvem rabdomiólise grave ou aumento das enzimas hepáticas, a suspensão temporária da terapia com estatinas é prudente.31,32 Além disso, se o paciente estiver em risco iminente de vida, a suspensão deve ser realizada, pelo menos até a recuperação da infecção.33

 Conclusões

O uso de estatinas é apoiado por uma literatura sólida, com inquestionáveis benefícios cardiovasculares. Apesar das evidências de que concentrações mais baixas de colesterol estão associadas a um curso mais grave de COVID-19, não há, entretanto, evidências de que as estatinas possam piorar o prognóstico. Ao contrário, essas drogas podem reduzir os mecanismos pró-inflamatórios e pró-trombóticos que caracterizam os casos mais graves de COVID-19. Atualmente, não existem evidências apoiando a descontinuação das estatinas em pacientes com COVID-19, exceto quando ocorrem elevações importantes das enzimas hepáticas, rabdomiólise ou risco de vida atribuído ao medicamento. Por outro lado, não há indicação para o uso desses medicamentos especificamente para prevenir complicações da infecção pelo SARS-CoV-2.

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Crit Care. 2020;24(1):429. Rodriguez-Nava G Trelles-Garcia DP Yanez-Bello MA Chung CW Trelles-Garcia VP Friedman HJ 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 17. Daniels LB, Sitapati AM, Zhang J, Zou J, Bui QM, Ren J, et al. Relation of statin use prior to admission to severity and recovery among COVID-19 inpatients. Am J Cardiol. 2020 Dec 1;136:149-55. Daniels LB Sitapati AM Zhang J Zou J Bui QM Ren J et al Relation of statin use prior to admission to severity and recovery among COVID-19 inpatients Am J Cardiol 2020 Dec 1 136 149 155 18. Song SL, Hays SB, Panton CE, Mylona EK, Kalligeros M, Shehadeh F, et al. Statin use is associated with decreased risk of invasive mechanical ventilation in COVID-19 patients: a preliminary study. pathogens. 2020;9(9):759. Song SL Hays SB Panton CE Mylona EK Kalligeros M Shehadeh F et al Statin use is associated with decreased risk of invasive mechanical ventilation in COVID-19 patients: a preliminary study pathogens 2020 9 9 759 19. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto Jr AM, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-207. Ridker PM Danielson E Fonseca FAH Genest J Gotto AM Jr Kastelein JJP et al Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein N Engl J Med 2008 359 21 2195 2207 20. Novack V, MacFadyen J, Malhotra A, Almog Y, Glynn RJ, Ridker PM. The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial. CMAJ. 2012;184(7):E367-72. Novack V MacFadyen J Malhotra A Almog Y Glynn RJ Ridker PM The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial CMAJ 2012 184 7 E367 E372 21. Helms J, Tacquard C, Severac F, Lorant IL, Ohana M, Delabranche X, et al. High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089-98. Helms J Tacquard C Severac F Lorant IL Ohana M Delabranche X et al High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Intensive Care Med 2020 46 6 1089 1098 22. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJP, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism: the JUPITER trial. N Engl J Med. 2009;360(18):1851-61. Glynn RJ Danielson E Fonseca FA Genest J Gotto AM Jr Kastelein JJP et al A randomized trial of rosuvastatin in the prevention of venous thromboembolism: the JUPITER trial N Engl J Med 2009 360 18 1851 1861 23. Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol. 2017;4(2):e83-93. Kunutsor SK Seidu S Khunti K Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis Lancet Haematol 2017 4 2 e83 e93 24. Adams NB, Lutsey PL, Folsom AR, Herrington DH, Sibley CT, Zakai NA, et al. Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis. J Thromb Haemost. 2013;11(6):1078-84. Adams NB Lutsey PL Folsom AR Herrington DH Sibley CT Zakai NA et al Statin therapy and levels of hemostatic factors in a healthy population: the Multi-Ethnic Study of Atherosclerosis J Thromb Haemost 2013 11 6 1078 1084 25. Rodriguez AL, Wojcik BM, Wrobleski SK, Myers Jr DD, Wakefield TW, Diaz JA. Statins, inflammation and deep vein thrombosis: a systematic review. J Thromb Thrombolysis. 2012;33(4):371-82. Rodriguez AL Wojcik BM Wrobleski SK Myers DD Jr Wakefield TW Diaz JA Statins, inflammation and deep vein thrombosis: a systematic review J Thromb Thrombolysis 2012 33 4 371 382 26. Bertoletti L, Couturaud F, Montani D, Parent F, Sanchez O. Venous thromboembolism and COVID-19. Respir Med Res. 2020 Nov;78:100759. Bertoletti L Couturaud F Montani D Parent F Sanchez O Venous thromboembolism and COVID-19 Respir Med Res 2020 78 100759 27. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81. Cholesterol Treatment Trialists’ (CTT) Collaboration Baigent C Blackwell L Emberson J Holland LE Reith C et al Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials Lancet 2010 376 9753 1670 1681 28. Sposito AC, Carvalho LS, Cintra RM, Araújo ALR, Ono AH, Andrade JM, et al. Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal. Atherosclerosis. 2009;207(1):191-4. Sposito AC Carvalho LS Cintra RM Araújo ALR Ono AH Andrade JM et al Rebound inflammatory response during the acute phase of myocardial infarction after simvastatin withdrawal Atherosclerosis 2009 207 1 191 194 29. PRISM Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina: the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. N Engl J Med. 1998;338(21):1498-505. PRISM Investigators A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina: the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators N Engl J Med 1998 338 21 1498 1505 30. Heeschen C, Hamm CW, Laufs U, Snapinn S, Böhm M, White HD, et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105(12):1446-52. Heeschen C Hamm CW Laufs U Snapinn S Böhm M White HD et al Withdrawal of statins increases event rates in patients with acute coronary syndromes Circulation 2002 105 12 1446 1452 31. European Society of Cardiology. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic; 2020. [citado 31 jul. 2020]. Disponível em: <https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance>. European Society of Cardiology ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic 2020 citado 31 jul. 2020 https://www.escardio.org/Education/COVID-19-and-Cardiology/ESC-COVID-19-Guidance> 32. Subir R, Jagat JM, Kalyan KG. Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19). Diabetes Metab Syndr. 2020;14(5):1225-9. Subir R Jagat JM Kalyan KG Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19) Diabetes Metab Syndr 2020 14 5 1225 1229 33. Greenhalgh T, Koh GCH, Car J. Covid-19: a remote assessment in primary care. BMJ. 2020 Mar 25;368:m1182. Greenhalgh T Koh GCH Car J Covid-19: a remote assessment in primary care BMJ 2020 Mar 25 368 m1182

Vinculação Acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Fontes de Financiamento

Filipe Ferrari recebe suporte financeiro pela Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Código 001. Raul D. Santos é bolsista do Conselho Nacional de Pesquisa e Desenvolvimento Tecnológico (CNPq), Brasil, nº 303734/2018-3.

 Research Letter Statins and COVID-19: To Suspend or Not to Suspend? That is the Question! 0000-0001-6929-8392 Ferrari Filipe 1 Santos Raul D. 2 3 Brazil Graduate Program in Cardiology and Cardiovascular Sciences, Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS – Brazil Brazil Lipid Clinic Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, SP – Brazil Brazil Hospital Israelita Albert Einstein, São Paulo, SP – Brazil Mailing Address: Raul D. Santos • Av. Albert Einstein, 627. CEP 05652-900, São Paulo, SP - Brasil E-mail: rauldsf@gmail.com

Author Contributions

Conception and design of the research, Acquisition of data, Analysis and interpretation of the data and Writing of the manuscript: Ferrari F, Santos RD; Critical revision of the manuscript for intellectual content: Santos RD.

Potential Conflict of Interest

RDS has received honoraria related to consulting, research and/or speaker activities from: Aché, Amgen, AstraZeneca, Esperion, Kowa, Novo Nordisk, Merck, MSD, Pfizer, PTC and Sanofi/Regeneron.

 COVID-19 Coronavirus Betacoronavirus Pandemics Cholesterol Dyslipidemias Infection Dydroxymethylglutaryl-CoA Reductase Inhibitors Lipoproteins Introduction

In the midst of so many uncertainties that permeate the new coronavirus disease 2019 (COVID-19), the evidence relating the presence of dyslipidemia to disease severity and consequent prognostic implications are still scarce. In May 2020, a retrospective Chinese study investigated the association between changes in cholesterol levels and prognosis in approximately 600 patients with COVID-19, who were paired by age and sex with healthy controls. First, it was observed that low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels were significantly lower in patients with COVID-19. Second, there was a trend for LDL-C and total cholesterol levels to decrease as the severity of infection increased (mild, severe, and critical, respectively).1 In that study, high-density lipoprotein cholesterol (HDL-C) levels were also decreased in severe cases. Similar data were observed by Fan et al.,2where levels of LDL-C were inversely associated with the severity of COVID-19. These data suggested a possible relation between low cholesterol levels and worsening of COVID-19 infection. In addition, experimental studies have shown that statins might increase the abundance of the angiotensin-converting enzyme 2 (ACE2), which could in part contribute to the entry of the virus into the cell and increase the risk of infectivity.3

Based on these previous findings, it was hypothesized that use of lipid-lowering therapies like statins could aggravate COVID-19 infection. However, it is known that serum cholesterol levels may drop in patients with active viral or bacterial infections,4,5 since LDL and HDL have a role in the immune system.6 On the other hand, hyperlipidemia can compromise the immune response and further exacerbate the inflammatory status of COVID-19 patients, increasing cardiovascular risk.7So, the question that ensues is, should statins be suspended or not in patients with COVID-19?

COVID-19, Infections, Thrombosis, and Statins Evidence of Potential Benefit

In addition to lowering pro-atherogenic lipoproteins, statins have other well-documented systemic effects, such as improvement in endothelial dysfunction, as well as anti-inflammatory and anti-thrombotic properties that lead to stabilization of atherosclerotic plaques.8Meta-analyses of randomized clinical trials have shown that statins can significantly reduce concentrations of C-reactive protein,9 von Willebrand factor antigen,10 and endothelin-1.11

An observational study with 3,043 patients hospitalized for the influenza virus found a lower risk of mortality in those using statins, before or during hospitalization (adjusted odds ratio [OR] 0.59).12Benefit from statins was also observed in hospitalized patients with viral pneumonia, resulting in lower mortality and need for intubation (OR 0.26).13

Given the pro-inflammatory and pro-thrombotic status observed in patients with more severe COVID-19, the characteristics of these drugs may be important for these patients.

Table 1 shows details of some studies examining the effects of statins in patients with viral infections and COVID-19.

– Evidence of Possible Benefits of Statins in the Viral Disease Scenario, as well as in COVID-19
Study Study Design Patients and Disease Total (N) Mean Age Adjustment for Covariates Results
Vandermeer et al. 201112 Multistate Patients hospitalized with influenza virus infections 3,043 70 years Age, race, CVD, lung and renal disease, influenza vaccination, and antiviral administration

Statins prior or during hospitalization versus no statin were associated with a protective odds of death within 30 days

Adjusted OR 0.59; 95% CI, 0.30 to 0.92
Henry et al. 201813 Retrospective Patients with viral pneumonia 539 64 years NA

Statins continued in hospital versus discontinuation reduced death and/or need of intubation throughout the hospital stay

OR 0.26; 95% CI, 0.08 to 0.81; P = 0.02
De Spiegeleer et al. 202014 Retrospective multicenter cohort COVID-19–positive subjects 154 86 years Age, sex, functional status, hypertension, and diabetes mellitus

The use of statins was related to the absence of symptoms during COVID-19

OR 2.91; 95% CI, 1.27 to 6.71; P = 0.011

Adjusted OR 2.65; 95% CI, 1.13 to 6.68; P = 0.028
Zhang et al. 202015 Retrospective Patients hospitalized for COVID-19 13,981 58 years Age, sex, and SpO2 at admission

Use of statins versus no statin was correlated to the reduction in the risk for 28-day all-cause mortality

Adjusted HR 0.58; 95% CI, 0.43 to 0.80; P = 0.001
Rodriguez-Nava et al. 202016 Retrospective cohort Patients with COVID-19 admitted to intensive care unit 87 68 years Age, hypertension, CVD, invasive mechanical ventilation, respiratory rate > 30, SpO2 < 94%, PaO2/FiO2 < 300 mmHg or lung infiltrates > 50%, number of comorbidities, and other adjuvant therapies (including hydroxychloroquine, intravenous steroids, azithromycin, tocilizumab, colchicine, and antibiotics)

The use of statin (specifically atorvastatin) has reduced the progression to death

Adjusted HR 0.38, 95% CI, 0.18 to 0.77; P = 0.008
Daniels et al. 202017 Retrospective single-center Patients hospitalized for COVID-19 170 59 years Age, sex, obesity, hypertension, diabetes, chronic kidney disease and CVD

Use of statins prior to admission reduced development of severe disease

Adjusted OR 0.29; 95% CI, 0.11 to 0.71; p = 0.009

Statin use increased rate of recovery from COVID-19 among subjects who had not yet experienced severe disease

Cause-specific adjusted HR for recovery 2.69; 95% CI, 1.36 to 5.33; p = 0.004
Song et al. 202018 Retrospective cohort Patients hospitalized for COVID-19 249 62 years Age, sex, race, CVD, chronic pulmonary disease, diabetes, and obesity

Statin use decreased risk for invasive mechanical ventilation

Adjusted OR 0.45; 95% CI, 0.20 to 0.99; p = 0.048

OR: odds ratio; HR: hazard ratio; CI: confidence interval; SpO2: peripheral oxygen saturation; CVD: cardiovascular disease; NA: not applicable.

In a retrospective cohort study from Belgium, De Spiegeleer et al.14 evaluated 154 elderly people (mean age: 86 years) who contracted COVID-19, and observed a significant trend for absence of symptoms in those previously taking statins (OR 2.91; 95% confidence interval (CI), 1.27 to 6.71). This remained statistically significant even after adjusting for covariates (OR 2.65; 95% CI, 1.13 to 6.68).

Another retrospective study of approximately 14,000 patients with COVID-19 found a lower risk of mortality with previous use of statins. In this study, 1,219 patients were receiving statins, and the all-cause mortality at 28 days in this group was 5.2%, while in the non-statin group it was 9.4% (adjusted hazard ratio [HR] 0.58; 95% CI, 0.43 to 0.80; p = 0.001).15 In another study with 87 patients with COVID-19 admitted to the intensive care unit, a slower progression to death was found in those receiving atorvastatin.16

Daniels et al.,17 through a retrospective single-center study, found a reduced risk of severe COVID-19 in patients who were using statins prior to admission (adjusted OR 0.29), and a faster time to recovery among those without severe disease (HR adjusted for recovery 2.69). In addition, in a retrospective cohort study of patients hospitalized with COVID-19 (N = 249) in the United States, the use of statins correlated with decreased risk for invasive mechanical ventilation (adjusted OR 0.45).18

Of course, the quoted studies are severely limited by their retrospective design; these data, despite being favorable to use of statins in viral infections, are only hypothesis generating, and they may be subject to a selection bias of individuals receiving better care. The question that ensues is, would there be any evidence that statins may prevent infectious diseases? In a post hoc analysis of patients included in the JUPITER trial,19which randomized 17,802 individuals with LDL-C < 130 mg/dL and high-sensitivity C-reactive protein ≥2.0 mg/L to receive rosuvastatin 20 mg/day or placebo followed for a median of 1.9 years, Novack et al.20 observed that the use of statins reduced, albeit modestly, the incidence of pneumonia (HR 0.83, 95% CI, 0.69 to 1.00). These results, which deserve to be proven in an adequately designed trial, suggest that statins may reduce pneumonia risk due to possible beneficial mild anti-inflammatory, antioxidant, immunomodulatory, anti-apoptotic, and endothelial effects according to the authors.18Whether this would benefit patients with COVID-19 is uncertain.

In addition to pulmonary complications, SARS-CoV-2 may also induce thrombosis.21 Would statins have beneficial effects in these cases? In a pre-specified analysis of the same JUPITER trial,19 the impact of rosuvastatin on the first occurrence of pulmonary embolism or venous thromboembolism was analyzed. Although there were no differences in the rates of pulmonary embolism between the groups (rosuvastatin and placebo), the group that received the statin showed a 43% reduction in the rates of venous thromboembolism (HR 0.57; 95% CI, 0.37 to 0.86; p = 0.007).22 Furthermore, a study-level meta-analysis of 13 observational cohort studies (N = 3,148,259) and 23 randomized clinical trials (N = 118,464) showed that, in both observational cohort studies and randomized clinical trials, there was a reduction in risk of deep venous thromboembolism but not of pulmonary embolism, when statin use was compared with controls (relative risk [RR] 0.75; 95% CI, 0.65 to 0.87; p < 0.0001; 0.85; 95% CI, 0.73 to 0.99; p = 0.038). A greater benefit was also found for the risk of venous thromboembolism with the use of rosuvastatin compared to other statins (RR 0.57; 95% CI, 0.22 to 0.75; p = 0.015).23Possible mechanisms to explain these results include the effects of statins on pro-thrombotic factors, such as reduced D-dimer, factor VIII,24 plasminogen activator inhibitor 1, and tissue factor levels, as well as decreased platelet aggregation and increased expression of thrombomodulin.25Figure 1 presents some proposed mechanisms where statins may act as antithrombotic and anti-inflammatory agents and could exert favorable effects in patients with COVID-19.

– Some proposed mechanisms for statins to reduce pro-inflammatory and prothrombotic state in patients with COVID-19.<xref ref-type="bibr" rid="B8"><sup>8</sup></xref>-<xref ref-type="bibr" rid="B11"><sup>11</sup></xref>,<xref ref-type="bibr" rid="B24"><sup>24</sup></xref>,<xref ref-type="bibr" rid="B25"><sup>25</sup></xref> HMG-CoA reductase: 3-hydroxy-3-methylglutaryl-CoA reductase; NF-κB: nuclear factor kappa B; VWF: von Willebrand factor.

Since a non-negligible portion of patients infected by SARS-CoV-2 (especially the more severe patients) may present alterations in the coagulation system and a high rate of venous thromboembolism,26 the maintenance of statins may improve these individuals’ prognosis. However, similarly to the possible anti-infectious properties, this also needs to be confirmed in randomized clinical trials.

 Statin Suspension and Increased Risk of Cardiovascular Events?

The concern that low cholesterol levels could be deleterious to patients with COVID-19 may lead to inappropriate suspension of lipid lowering medications in patients at high risk of cardiovascular disease. Statins are the cornerstone for lipid lowering therapy with the aim of reducing the risk of coronary artery disease (CAD); as a group, statins are one of the most prescribed drugs in the world. The Cholesterol Treatment Trialists Meta-analysis (CTT)27showed that for each 1.0 mmol/L (~ 40 mg/dL) reduction of LDL-C, all-cause mortality was reduced by 10% (RR 0.90, 95% CI, 0.87 to 0.93; p < 0.0001), in addition to a 20% reduction in CAD deaths (RR 0.80; 99% CI, 0.74 to 0.87; p < 0.0001).

An important scenario where statin suspension could be deleterious is during the early period after an acute coronary syndrome event. In this scenario, the addition and maintenance of statins are fundamental, and drug suspension may increase patients’ risks. In this sense, a Brazilian observational study with 249 patients observed a rebound inflammatory effect in the acute phase of myocardial infarction (MI) after statin withdrawal. Sposito et al.28found that, at the beginning of the study, those who were receiving statins had lower C-reactive protein values when compared to those who were not, before the onset of MI. On the fifth day after MI, median C-reactive protein was significantly higher in the group where statins had been suspended.28 In addition, in an analysis of patients presenting with CAD and chest pain within the last 24 hours in the PRISM study29 (N = 1,616), Heeschen et al.30reported that the use of statins reduced the rate of events after 30 days, compared to patients without those medications (adjusted HR 0.49, 95% CI, 0.21 to 0.86). When statins were suspended after admission, cardiac risk increased (OR 2.93; 95% CI, 1.64 to 6.27; p = 0,005), and, although it was not statistically significant, there was a trend to greater risk compared to patients who had never received statins (OR 1.69; 95% CI, 0.92 to 3.56).29 Therefore, the withdrawal of these drugs should be viewed with extreme caution, especially after an acute coronary event, since this may lead to appearance of complications, worsening patients’ prognosis.

In short, the use of statins is based on solid and robust literature, and their discontinuation, except for medical indication, may lead to acute events, further increasing the risk of patients infected by COVID-19, especially of those in secondary prevention and those who have had a recent acute coronary event. Physicians and patients should keep this knowledge in mind.

 When Should We Consider Suspending the Statins in Patients with COVID-19?

According to European Society of Cardiology guidelines, in rare cases where patients with COVID-19 develop severe rhabdomyolysis or increased liver enzymes, temporary suspension of statin therapy is prudent.31,32 Furthermore, if the patient is at imminent risk of life, suspension should be carried out, at least until recovery from the infection.33

 Conclusions

The use of statins is supported by solid literature, with unquestionable cardiovascular benefits. Despite evidence that lower cholesterol concentrations are associated with more severe course of COVID-19, there is, however, no evidence that statins may worsen prognosis. On the contrary, these drugs may reduce the pro-inflammatory and pro-thrombotic mechanisms that characterize more severe cases of COVID-19. Currently, there is no evidence to support discontinuation of statins in patients with COVID-19, except when important elevations of hepatic enzymes, rhabdomyolysis, or drug-attributed risk of life occur. On the other hand, there is no indication for the use of these drugs specifically to prevent complications of SARS-CoV-2 infection.

Study Association

This study is not associated with any thesis or dissertation work.

Sources of Funding

Filipe Ferrari receives financial support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Funding Code 001. Raul D. Santos is a recipient of a Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq) research scholarship (filing #303734/2018-3).