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Statin Treatment of COVID-19

Published:September 26, 2020DOI:https://doi.org/10.1016/j.amjcard.2020.09.050
      In a recent meta-analysis of 4 observational studies, Kow and Hasan reported that statins were 30% effective in reducing the severity or mortality of COVID-19.
      • Kow CS
      • Hasan SS.
      Meta-analysis of effectiveness of statins in patients with severe COVID-19.
      • Yan H
      • Valdes AM
      • Vijay A
      Role of drugs affecting the renin-angiotensin-aldosterone system on susceptibility and severity of COVID-19: a large case-control study from Zheijang Province, China.
      • 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.
      • Grasselli G
      • Greco M
      • Zanella A
      • Albano G
      • Antonelli M
      • Bellani G
      • Bonanomi E
      • Cabrini L
      • Carlesso E
      • Castelli G
      • Cattaneo S
      • Cereda D
      • Colombo S
      • Coluccello A
      • Crescini G
      • Forastieri Molinari A
      • Foti G
      • Fumagalli R
      • Iotti GA
      • Langer T
      • Latronico N
      • Lorini FL
      • Mojoli F
      • Natalini G
      • Pessina CM
      • Ranieri VM
      • Rech R
      • Scudeller L
      • Rosano A
      • Storti E
      • Thompson BT
      • Tirani M
      • Villani PG
      • Pesenti A
      • Cecconi M
      COVID-19 Lombardy ICU Network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      • Zhang XJ
      • Qin JJ
      • Cheng X
      • Shen L
      • Zhao YC
      • Yuan Y
      • Lei F
      • Chen MM
      • Yang H
      • Bai L
      • Song X
      • Lin L
      • Xia M
      • Zhou F
      • Zhou J
      • She ZG
      • Zhu L
      • Ma X
      • Xu Q
      • Ye P
      • Chen G
      • Liu L
      • Mao W
      • Yan Y
      • Xiao B
      • Lu Z
      • Peng G
      • Liu M
      • Yang J
      • Yang L
      • Zhang C
      • Lu H
      • Xia X
      • Wang D
      • Liao X
      • Wei X
      • Zhang BH
      • Zhang X
      • Yang J
      • Zhao GN
      • Zhang P
      • Liu PP
      • Loomba R
      • Ji YX
      • Xia J
      • Wang Y
      • Cai J
      • Guo J
      • Li H
      In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19.
      Since their report was published, 2 additional observational studies have appeared.

      Gupta A, Madhavan MV, Poterucha TJ, DeFilippis EM, Hennessey JA, Redfors B, Eckhardt C, Bikdeli B, Platt J, Nalbandian A, Elias P, Cummings MJ, Houri SN, Lawlor M, Ranard LS, Li J, Boyle C, Givens R, Brodie D, Krumholz HM, Stone GW, Sethi SS, Burkhoff D, Uriel N, Schwartz A, Leon MB, Kirtane AJ, Wan EY, Parikh SA. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Res Sq, doi.org/10.21203/rs.3.rs-56210/v1.1.

      ,
      • De Spiegeleer A
      • Bronselaer A
      • Teo JT
      • Byttebier G
      • De Tre G
      • Belmans L
      • Dobson R
      • Wynendaele E
      • Van De Wiele C
      • Vandaele F
      • Van Dijck D
      • Bean D
      • Fedson D
      • De Spiegeleer B
      The effects of ARBs, ACEis, and statins on clinical outcomes of COVID-19 infection among nursing home residents.
      Most of these 6 studies reported on statin treatment in reducing 30-day mortality (Table 1). However, Kow and Hasan considered studies in which patients received statins either as outpatients or inpatients (Table 1). For this reason, their estimate of statin effectiveness was probably imprecise.
      Table 1Statin treatment and 28-30-day COVID-19 mortality
      Study, type (ref)Statin treatment Outpatient/InpatientControls/treated (no.)Adjusted hazard ratio95% CIp value
      Yan, cohort (2)
      The study by Yan et al evaluated the effect of statin treatment in reducing the severity of COVID-19, not its mortality.
      Outpatient482/1280.980.32-2.990.97
      Rodriguez-Nava, cohort, ICU (3)Inpatient39/480.380.18-0.770.008
      Grasselli, cohort (4)Outpatient2,062/1,9260.980.81-1.200.87
      Zhang, PSM, 4:1 (5)Inpatient3,444/8610.580.43-0.800.001
      Gupta, PSM (6)Outpatient648/6480.490.38-0.63<0.001
      de Spiegleer, cohort, NH (7)
      The study by de Spiegeleer et al evaluated residents of nursing homes who either died in hospital or experienced hospital stays ≥7 days.
      Inpatient133/310.510.14-1.350.209
      CI = confidence interval; ICU = intensive care unit; PSM = propensity score matched.
      low asterisk The study by Yan et al evaluated the effect of statin treatment in reducing the severity of COVID-19, not its mortality.
      The study by de Spiegeleer et al evaluated residents of nursing homes who either died in hospital or experienced hospital stays ≥7 days.
      Statins are known to downregulate inflammatory cytokines and other biomarkers of inflammation.
      • Oesterle A
      • Laufs U
      • Liao JK
      Pleiotropic effects of statins on the cardiovascular system.
      Studies in human volunteers showed that these effects occur in a matter of a few hours or a day or 2.
      • Shyamsundar M
      • McKeown STW
      • O'Kane CM
      • Craig TR
      • Brown V
      • Thickett DR
      • Matthay MA
      • Taggart CC
      • Backman JT
      • Elborn JS
      • McAuley DF
      Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers.
      Moreover, in patients who have been taking statins, withdrawing treatment is followed by a rebound that increases both cytokine levels and mortality.
      • Fonarow GC
      • Wright RS
      • Spencer FA
      • Fredrick FA
      • Dong W
      • Every N
      • French WJ
      National Registry of Myocardial Infarction 4 Investigators, Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality.
      ,
      • Cubeddu LX
      • Seamon MJ
      Statin withdrawal: clinical implications and molecular mechanisms.
      Yan et al and Grasselli et al did not report on whether outpatient statin treatment was continued after hospital admission.
      • Yan H
      • Valdes AM
      • Vijay A
      Role of drugs affecting the renin-angiotensin-aldosterone system on susceptibility and severity of COVID-19: a large case-control study from Zheijang Province, China.
      ,
      • Grasselli G
      • Greco M
      • Zanella A
      • Albano G
      • Antonelli M
      • Bellani G
      • Bonanomi E
      • Cabrini L
      • Carlesso E
      • Castelli G
      • Cattaneo S
      • Cereda D
      • Colombo S
      • Coluccello A
      • Crescini G
      • Forastieri Molinari A
      • Foti G
      • Fumagalli R
      • Iotti GA
      • Langer T
      • Latronico N
      • Lorini FL
      • Mojoli F
      • Natalini G
      • Pessina CM
      • Ranieri VM
      • Rech R
      • Scudeller L
      • Rosano A
      • Storti E
      • Thompson BT
      • Tirani M
      • Villani PG
      • Pesenti A
      • Cecconi M
      COVID-19 Lombardy ICU Network
      Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy.
      A recent report of statins treatment by Gupta et al was also based on outpatient records (Table 1).

      Gupta A, Madhavan MV, Poterucha TJ, DeFilippis EM, Hennessey JA, Redfors B, Eckhardt C, Bikdeli B, Platt J, Nalbandian A, Elias P, Cummings MJ, Houri SN, Lawlor M, Ranard LS, Li J, Boyle C, Givens R, Brodie D, Krumholz HM, Stone GW, Sethi SS, Burkhoff D, Uriel N, Schwartz A, Leon MB, Kirtane AJ, Wan EY, Parikh SA. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Res Sq, doi.org/10.21203/rs.3.rs-56210/v1.1.

      In this study, only 77% of outpatient statin users continued treatment as inpatients, which means that 23% of the group of statin outpatient users were at risk of a rebound effect and increased mortality after hospital admission. This could have led to an underestimate of survival in patients who received statins as inpatients.
      Two of the 4 studies reported by Kow and Hasan were correctly based on inpatient statin treatment and both showed statistically significant improvement in survival (Table 1).
      • 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.
      ,
      • Zhang XJ
      • Qin JJ
      • Cheng X
      • Shen L
      • Zhao YC
      • Yuan Y
      • Lei F
      • Chen MM
      • Yang H
      • Bai L
      • Song X
      • Lin L
      • Xia M
      • Zhou F
      • Zhou J
      • She ZG
      • Zhu L
      • Ma X
      • Xu Q
      • Ye P
      • Chen G
      • Liu L
      • Mao W
      • Yan Y
      • Xiao B
      • Lu Z
      • Peng G
      • Liu M
      • Yang J
      • Yang L
      • Zhang C
      • Lu H
      • Xia X
      • Wang D
      • Liao X
      • Wei X
      • Zhang BH
      • Zhang X
      • Yang J
      • Zhao GN
      • Zhang P
      • Liu PP
      • Loomba R
      • Ji YX
      • Xia J
      • Wang Y
      • Cai J
      • Guo J
      • Li H
      In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19.
      The smaller study by De Spiegleer et al also reported benefits in statin users among nursing home residents, but the result did not reach statistical significance.
      • De Spiegeleer A
      • Bronselaer A
      • Teo JT
      • Byttebier G
      • De Tre G
      • Belmans L
      • Dobson R
      • Wynendaele E
      • Van De Wiele C
      • Vandaele F
      • Van Dijck D
      • Bean D
      • Fedson D
      • De Spiegeleer B
      The effects of ARBs, ACEis, and statins on clinical outcomes of COVID-19 infection among nursing home residents.
      The largest and most detailed study of inpatient statin treatment by Zhang et al also reported that inpatient treatment with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not provide a survival benefit greater than that provided by statin treatment alone.
      • Zhang XJ
      • Qin JJ
      • Cheng X
      • Shen L
      • Zhao YC
      • Yuan Y
      • Lei F
      • Chen MM
      • Yang H
      • Bai L
      • Song X
      • Lin L
      • Xia M
      • Zhou F
      • Zhou J
      • She ZG
      • Zhu L
      • Ma X
      • Xu Q
      • Ye P
      • Chen G
      • Liu L
      • Mao W
      • Yan Y
      • Xiao B
      • Lu Z
      • Peng G
      • Liu M
      • Yang J
      • Yang L
      • Zhang C
      • Lu H
      • Xia X
      • Wang D
      • Liao X
      • Wei X
      • Zhang BH
      • Zhang X
      • Yang J
      • Zhao GN
      • Zhang P
      • Liu PP
      • Loomba R
      • Ji YX
      • Xia J
      • Wang Y
      • Cai J
      • Guo J
      • Li H
      In-hospital use of statins is associated with a reduced risk of mortality among individuals with COVID-19.
      Nonetheless, several reports have shown that in hypertensive COVID-19 patients, outpatient or inpatient treatment with ACEIs or ARBs is not harmful,
      • Yang G
      • Tan Z
      • Zhou L
      • Yang M
      • Peng L
      • Liu J
      • Cai J
      • Yang R
      • Han J
      • Huang Y
      • He S
      Effects of ARBs and ACEIs on virus infection, inflammatory status and clinical outcomes in COVID-19 patients with hypertension: a single center retrospective study.
      • Li J
      • Wang X
      • Chen J
      • Zhang H
      • Deng A
      Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China.
      • Zhang P
      • Zhu L
      • Cai J
      • Lei F
      • Qin JJ
      • Xie J
      • Liu YM
      • Zhao YC
      • Huang X
      • Lin L
      • Xia M
      • Chen MM
      • Cheng X
      • Zhang X
      • Guo D
      • Peng Y
      • Ji YX
      • Chen J
      • She ZG
      • Wang Y
      • Xu Q
      • Tan R
      • Wang H
      • Lin J
      • Luo P
      • Fu S
      • Cai H
      • Ye P
      • Xiao B
      • Mao W
      • Liu L
      • Yan Y
      • Liu M
      • Chen M
      • Zhang XJ
      • Wang X
      • Touyz RM
      • Xia J
      • Zhang BH
      • Huaeg X
      • Yuan Y
      • Rohit L
      • Liu PP
      • Li H
      Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19.
      and in some instances, these drugs actually improve survival.
      • Zhang P
      • Zhu L
      • Cai J
      • Lei F
      • Qin JJ
      • Xie J
      • Liu YM
      • Zhao YC
      • Huang X
      • Lin L
      • Xia M
      • Chen MM
      • Cheng X
      • Zhang X
      • Guo D
      • Peng Y
      • Ji YX
      • Chen J
      • She ZG
      • Wang Y
      • Xu Q
      • Tan R
      • Wang H
      • Lin J
      • Luo P
      • Fu S
      • Cai H
      • Ye P
      • Xiao B
      • Mao W
      • Liu L
      • Yan Y
      • Liu M
      • Chen M
      • Zhang XJ
      • Wang X
      • Touyz RM
      • Xia J
      • Zhang BH
      • Huaeg X
      • Yuan Y
      • Rohit L
      • Liu PP
      • Li H
      Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19.
      In addition, inpatient ACEI/ARB treatment can reduce levels of inflammatory biomarkers.
      • Yang G
      • Tan Z
      • Zhou L
      • Yang M
      • Peng L
      • Liu J
      • Cai J
      • Yang R
      • Han J
      • Huang Y
      • He S
      Effects of ARBs and ACEIs on virus infection, inflammatory status and clinical outcomes in COVID-19 patients with hypertension: a single center retrospective study.
      Importantly, survival was significantly better in COVID-19 patients whose ACEI/ARB outpatient treatment was continued in the hospital compared with those whose treatment was discontinued.
      • Lam KW
      • Chow KW
      • Vo J
      • Hou W
      • Li H
      • Richman PS
      • Mallipattu SK
      • Skopicki HA
      • Singer AJ
      • Duong TQ
      Continued in-hospital ACE inhibitor and ARB use in hypertensive COVID-19 patients is associated with positive clinical outcomes.
      This echoes the experience with statin withdrawal.
      Patients with COVID-19 experience severe endothelial dysfunction.
      • Gustafson D
      • Raju S
      • Wu R
      • et al.
      Overcoming barriers: the endothelium as a linchpin of coronavirus disease 2019 pathogenesis?.
      Statins and ARBs (and presumably ACEIs) have broad effects in maintaining or restoring normal endothelial cell function.
      • Fedson DS
      Treating the host response to emerging virus diseases: lesson learned from sepsis, pneumonia, influenza and Ebola.
      Combination treatment with both drugs has been suggested for cardiovascular diseases
      • Koh KK
      • Sakuma I
      • Shimada K
      • Hayashi T
      • Quon MJ
      Combining potent statin therapy with other drugs to optimize simultaneous cardiovascular and metabolic benefits while minimizing adverse events.
      and for emerging infectious diseases,
      • Fedson DS
      Treating the host response to emerging virus diseases: lesson learned from sepsis, pneumonia, influenza and Ebola.
      including Ebola and COVID-19.
      • Fedson DS
      A practical treatment for patients with Ebola virus disease.
      ,
      • Fedson DS
      • Opal SM
      • Rordam OM
      Hiding in plain sight; an approach to treating patients with severe COVID-19 infection.
      These drugs primarily target the host response to infection,
      • Pirofski L-a
      • Casadevall A
      Pathogenesis of COVID-19 from the perspective of the damage-response framework.
      not the viruses themselves.
      • Fedson DS
      Treating the host response to emerging virus diseases: lesson learned from sepsis, pneumonia, influenza and Ebola.
      • Koh KK
      • Sakuma I
      • Shimada K
      • Hayashi T
      • Quon MJ
      Combining potent statin therapy with other drugs to optimize simultaneous cardiovascular and metabolic benefits while minimizing adverse events.
      • Fedson DS
      A practical treatment for patients with Ebola virus disease.
      • Fedson DS
      • Opal SM
      • Rordam OM
      Hiding in plain sight; an approach to treating patients with severe COVID-19 infection.
      ,
      • Parihar SP
      • Guler R
      • Brombacher F
      Statins: a viable candidate for host-directed therapy against infectious diseases.
      Like dexamethasone, which has been shown in a randomized controlled trial to modestly improve survival in COVID-19 patients who require oxygen treatment or mechanical ventilation,
      • Horby P
      • Lim WS
      • Emberson JR
      • Mafham M
      • Bell JL
      • Linsell L
      • Staplin N
      • Brightling C
      • Ustianowski A
      • Elmahi E
      • Prudon B
      • Green C
      • Felton T
      • Chadwick D
      • Rege K
      • Fegan C
      • Chappell LC
      • Faust SN
      • Jaki T
      • Jeffery K
      • Montgomery A
      • Rowan K
      • Juszczak E
      • Baillie JK
      • Haynes R
      • Landray MJ
      RECOVERY Collaborative Group
      Dexamethasone in hospitalized patients with Covid-19 - preliminary report.
      they are available worldwide as inexpensive generic drugs and could be used on the first pandemic day in any country that has a basic healthcare system.
      Several randomized controlled trials of statins, ACEIs and ARBs are planned or are underway for COVID-19 patients, but most of them will not report results until 2021. In the meantime, many physicians will feel an immediate need to offer effective treatments for their COVID-19 patients.
      • Angus DC
      Optimizing the trade-off between learning and doing in a pandemic.
      The studies of inpatient statin treatment are supported by solid experimental and clinical findings,
      • Fedson DS
      Treating the host response to emerging virus diseases: lesson learned from sepsis, pneumonia, influenza and Ebola.
      but it is unclear whether they provide a sufficient basis on which physicians can decide how to treat their patients. Nonetheless, the studies summarized in Table 1, together with future observational reports on the effectiveness of inpatient treatment of COVID-19 patients with statins (and perhaps ACEIs/ARBs), will undoubtedly contribute to their treatment decisions.

      Disclosure

      The author has no conflicts of interest to disclose. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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