Simvastatin in Critically Ill Patients with Covid-19

the REMAP-CAP Investigators; Thomas E. Hills; Elizabeth Lorenzi; Lindsay R. Berry; Murali Shyamsundar; Farah Al-Beidh; Djillali Annane; Yaseen Arabi; Diptesh Aryal; Carly Au; Abigail Beane; Zahra Bhimani; Marc Bonten; Charlotte A. Bradbury; Frank M. Brunkhorst; Aidan Burrell; Meredith Buxton; Carolyn S. Calfee; Maurizio Cecconi; Allen C. Cheng; Matthew E. Cove; Michelle A. Detry; Lise J. Estcourt; Mark Fitzgerald; Ewan C. Goligher; Herman Goossens; Cameron Green; Rashan Haniffa; David A. Harrison; Madiha Hashmi; Alisa M. Higgins; David T. Huang; Nao Ichihara; Deva Jayakumar; Peter S. Kruger; Francois Lamontagne; Lamprini Lampro; Patrick R. Lawler; John C. Marshall; Alexina J. Mason; Anna McGlothlin; Shay McGuinness; Zoe K. McQuilten; Bryan J. McVerry; Paul R. Mouncey; Srinivas Murthy; Matthew D. Neal; Alistair D. Nichol; Cecilia M. O'Kane; Rachael L. Parke; Jane C. Parker; Ebenezer Rabindrarajan; Luis F. Reyes; Kathryn M. Rowan; Hiroki Saito; Marlene Santos; Christina T. Saunders; Christopher W. Seymour; Manu Shankar-Hari; Pratik Sinha; B. Taylor Thompson; Alexis F. Turgeon; Anne M. Turner; Frank Van De Veerdonk; Sebastian Weis; Ian S. Young; Ryan Zarychanski; Roger J. Lewis; Colin J. McArthur; Derek C. Angus; Scott M. Berry; Lennie P.G. Derde; Steve A. Webb; Anthony C. Gordon; Daniel F. McAuley

doi:10.1056/NEJMoa2309995

Simvastatin in Critically Ill Patients with Covid-19

the REMAP-CAP Investigators, Thomas E. Hills, Elizabeth Lorenzi, Lindsay R. Berry, Murali Shyamsundar, Farah Al-Beidh, Djillali Annane, Yaseen Arabi, Diptesh Aryal, Carly Au, Abigail Beane, Zahra Bhimani, Marc Bonten, Charlotte A. Bradbury, Frank M. Brunkhorst, Aidan Burrell, Meredith Buxton, Carolyn S. Calfee, Maurizio Cecconi, Allen C. ChengMatthew E. Cove, Michelle A. Detry, Lise J. Estcourt, Mark Fitzgerald, Ewan C. Goligher, Herman Goossens, Cameron Green, Rashan Haniffa, David A. Harrison, Madiha Hashmi, Alisa M. Higgins, David T. Huang, Nao Ichihara, Deva Jayakumar, Peter S. Kruger, Francois Lamontagne, Lamprini Lampro, Patrick R. Lawler, John C. Marshall, Alexina J. Mason, Anna McGlothlin, Shay McGuinness, Zoe K. McQuilten, Bryan J. McVerry, Paul R. Mouncey, Srinivas Murthy, Matthew D. Neal, Alistair D. Nichol, Cecilia M. O'Kane, Rachael L. Parke, Jane C. Parker, Ebenezer Rabindrarajan, Luis F. Reyes, Kathryn M. Rowan, Hiroki Saito, Marlene Santos, Christina T. Saunders, Christopher W. Seymour, Manu Shankar-Hari, Pratik Sinha, B. Taylor Thompson, Alexis F. Turgeon, Anne M. Turner, Frank Van De Veerdonk, Sebastian Weis, Ian S. Young, Ryan Zarychanski, Roger J. Lewis, Colin J. McArthur, Derek C. Angus, Scott M. Berry, Lennie P.G. Derde, Steve A. Webb, Anthony C. Gordon, Daniel F. McAuley

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Abstract

Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control.

Original language	English
Pages (from-to)	2341-2354
Number of pages	14
Journal	New England Journal of Medicine
Volume	389
Issue number	25
DOIs	https://doi.org/10.1056/NEJMoa2309995
State	Published - Dec 21 2023

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10.1056/NEJMoa2309995

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the REMAP-CAP Investigators, Hills, T. E., Lorenzi, E., Berry, L. R., Shyamsundar, M., Al-Beidh, F., Annane, D., Arabi, Y., Aryal, D., Au, C., Beane, A., Bhimani, Z., Bonten, M., Bradbury, C. A., Brunkhorst, F. M., Burrell, A., Buxton, M., Calfee, C. S., Cecconi, M., ... McAuley, D. F. (2023). Simvastatin in Critically Ill Patients with Covid-19. New England Journal of Medicine, 389(25), 2341-2354. https://doi.org/10.1056/NEJMoa2309995

@article{b595a773994042b787e792686c4c35bf,

title = "Simvastatin in Critically Ill Patients with Covid-19",

abstract = "Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control.",

author = "{the REMAP-CAP Investigators} and Hills, {Thomas E.} and Elizabeth Lorenzi and Berry, {Lindsay R.} and Murali Shyamsundar and Farah Al-Beidh and Djillali Annane and Yaseen Arabi and Diptesh Aryal and Carly Au and Abigail Beane and Zahra Bhimani and Marc Bonten and Bradbury, {Charlotte A.} and Brunkhorst, {Frank M.} and Aidan Burrell and Meredith Buxton and Calfee, {Carolyn S.} and Maurizio Cecconi and Cheng, {Allen C.} and Cove, {Matthew E.} and Detry, {Michelle A.} and Estcourt, {Lise J.} and Mark Fitzgerald and Goligher, {Ewan C.} and Herman Goossens and Cameron Green and Rashan Haniffa and Harrison, {David A.} and Madiha Hashmi and Higgins, {Alisa M.} and Huang, {David T.} and Nao Ichihara and Deva Jayakumar and Kruger, {Peter S.} and Francois Lamontagne and Lamprini Lampro and Lawler, {Patrick R.} and Marshall, {John C.} and Mason, {Alexina J.} and Anna McGlothlin and Shay McGuinness and McQuilten, {Zoe K.} and McVerry, {Bryan J.} and Mouncey, {Paul R.} and Srinivas Murthy and Neal, {Matthew D.} and Nichol, {Alistair D.} and O'Kane, {Cecilia M.} and Parke, {Rachael L.} and Parker, {Jane C.} and Ebenezer Rabindrarajan and Reyes, {Luis F.} and Rowan, {Kathryn M.} and Hiroki Saito and Marlene Santos and Saunders, {Christina T.} and Seymour, {Christopher W.} and Manu Shankar-Hari and Pratik Sinha and Thompson, {B. Taylor} and Turgeon, {Alexis F.} and Turner, {Anne M.} and {Van De Veerdonk}, Frank and Sebastian Weis and Young, {Ian S.} and Ryan Zarychanski and Lewis, {Roger J.} and McArthur, {Colin J.} and Angus, {Derek C.} and Berry, {Scott M.} and Derde, {Lennie P.G.} and Webb, {Steve A.} and Gordon, {Anthony C.} and McAuley, {Daniel F.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2023 Massachusetts Medical Society.",

year = "2023",

month = dec,

day = "21",

doi = "10.1056/NEJMoa2309995",

language = "English",

volume = "389",

pages = "2341--2354",

journal = "New England Journal of Medicine",

issn = "0028-4793",

number = "25",

}

the REMAP-CAP Investigators, Hills, TE, Lorenzi, E, Berry, LR, Shyamsundar, M, Al-Beidh, F, Annane, D, Arabi, Y, Aryal, D, Au, C, Beane, A, Bhimani, Z, Bonten, M, Bradbury, CA, Brunkhorst, FM, Burrell, A, Buxton, M, Calfee, CS, Cecconi, M, Cheng, AC, Cove, ME, Detry, MA, Estcourt, LJ, Fitzgerald, M, Goligher, EC, Goossens, H, Green, C, Haniffa, R, Harrison, DA, Hashmi, M, Higgins, AM, Huang, DT, Ichihara, N, Jayakumar, D, Kruger, PS, Lamontagne, F, Lampro, L, Lawler, PR, Marshall, JC, Mason, AJ, McGlothlin, A, McGuinness, S, McQuilten, ZK, McVerry, BJ, Mouncey, PR, Murthy, S, Neal, MD, Nichol, AD, O'Kane, CM, Parke, RL, Parker, JC, Rabindrarajan, E, Reyes, LF, Rowan, KM, Saito, H, Santos, M, Saunders, CT, Seymour, CW, Shankar-Hari, M, Sinha, P, Thompson, BT, Turgeon, AF, Turner, AM, Van De Veerdonk, F, Weis, S, Young, IS, Zarychanski, R, Lewis, RJ, McArthur, CJ, Angus, DC, Berry, SM, Derde, LPG, Webb, SA, Gordon, AC & McAuley, DF 2023, 'Simvastatin in Critically Ill Patients with Covid-19', New England Journal of Medicine, vol. 389, no. 25, pp. 2341-2354. https://doi.org/10.1056/NEJMoa2309995

TY - JOUR

T1 - Simvastatin in Critically Ill Patients with Covid-19

AU - the REMAP-CAP Investigators

AU - Hills, Thomas E.

AU - Lorenzi, Elizabeth

AU - Berry, Lindsay R.

AU - Shyamsundar, Murali

AU - Al-Beidh, Farah

AU - Annane, Djillali

AU - Arabi, Yaseen

AU - Aryal, Diptesh

AU - Au, Carly

AU - Beane, Abigail

AU - Bhimani, Zahra

AU - Bonten, Marc

AU - Bradbury, Charlotte A.

AU - Brunkhorst, Frank M.

AU - Burrell, Aidan

AU - Buxton, Meredith

AU - Calfee, Carolyn S.

AU - Cecconi, Maurizio

AU - Cheng, Allen C.

AU - Cove, Matthew E.

AU - Detry, Michelle A.

AU - Estcourt, Lise J.

AU - Fitzgerald, Mark

AU - Goligher, Ewan C.

AU - Goossens, Herman

AU - Green, Cameron

AU - Haniffa, Rashan

AU - Harrison, David A.

AU - Hashmi, Madiha

AU - Higgins, Alisa M.

AU - Huang, David T.

AU - Ichihara, Nao

AU - Jayakumar, Deva

AU - Kruger, Peter S.

AU - Lamontagne, Francois

AU - Lampro, Lamprini

AU - Lawler, Patrick R.

AU - Marshall, John C.

AU - Mason, Alexina J.

AU - McGlothlin, Anna

AU - McGuinness, Shay

AU - McQuilten, Zoe K.

AU - McVerry, Bryan J.

AU - Mouncey, Paul R.

AU - Murthy, Srinivas

AU - Neal, Matthew D.

AU - Nichol, Alistair D.

AU - O'Kane, Cecilia M.

AU - Parke, Rachael L.

AU - Parker, Jane C.

AU - Rabindrarajan, Ebenezer

AU - Reyes, Luis F.

AU - Rowan, Kathryn M.

AU - Saito, Hiroki

AU - Santos, Marlene

AU - Saunders, Christina T.

AU - Seymour, Christopher W.

AU - Shankar-Hari, Manu

AU - Sinha, Pratik

AU - Thompson, B. Taylor

AU - Turgeon, Alexis F.

AU - Turner, Anne M.

AU - Van De Veerdonk, Frank

AU - Weis, Sebastian

AU - Young, Ian S.

AU - Zarychanski, Ryan

AU - Lewis, Roger J.

AU - McArthur, Colin J.

AU - Angus, Derek C.

AU - Berry, Scott M.

AU - Derde, Lennie P.G.

AU - Webb, Steve A.

AU - Gordon, Anthony C.

AU - McAuley, Daniel F.

PY - 2023/12/21

Y1 - 2023/12/21

N2 - Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control.

AB - Background: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2). Results: Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support-free days was 11 (interquartile range, -1 to 17) in the simvastatin group and 7 (interquartile range, -1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control. Conclusions: Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control.

UR - http://www.scopus.com/inward/record.url?scp=85180969813&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa2309995

DO - 10.1056/NEJMoa2309995

M3 - Article

C2 - 37888913

AN - SCOPUS:85180969813

SN - 0028-4793

VL - 389

SP - 2341

EP - 2354

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 25

ER -

Simvastatin in Critically Ill Patients with Covid-19

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