Simvastatin in the acute respiratory distress syndrome.
Author(s): McAuley DF(1), Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, Johnston
P, Hopkins PA, Johnston AJ, McDowell C, McNally C; HARP-2 Investigators; Irish
Critical Care Trials Group.
Collaborators: Johnston AJ, Paikray A, Yates C, Polgarova P, Price E, McInerney
A, Zamoscik K, Dempsey G, Seasman C, Gilfeather L, Hemmings N, O'Kane S, Johnston
P, Pokorny L, Nutt C, O'Neill O, Prashast P, Smalley C, Jacob R, O'Rourke J,
Sultan SF, Schilling C, Perkins GD, Melody T, Couper K, Daniels R, Gao F, Hull J,
Gould T, Thomas M, Sweet K, Breen D, Neau E, Peel WJ, Jardine C, Jefferson P,
Wright SE, Harris K, Thomas M, Hierons S, Laffey J, Scully M, McInerney V, Jafaar
R, Camporota L, Lei K, Kaul S, Chivburi M, Gratix A, Bennett R, Martinson V,
Sleight L, Smith N, Hopkins PA, Hadfield D, Casboult S, Wade-Smith F, Dawson J,
Mellis C, Harris C, Parsons G, Helyar S, Bodenham AR, Elliott S, Beardow Z, Birch
S, Marsh B, Martin T, Dhrampal A, Rosbergen M, Webb S, Bottrill F, Reschreiter H,
Barcraft-Barnes H, Camsooksai J, Johnston A, Clarkson A, Bentley C, Cooper L, Qui
Y, Mitchell N, Carrera R, Whitehouse A, Danbury CM, Jacques N, Brown A, Rogerson
D, Morris C, Walsh T, Gillies M, Price G, Kefala K, Young N, Hope D, McCulloch C,
Antonelli J, Ramsay P, Everingham K, Boardman L, Dawson H, Pollock F, Thompson J,
Welters ID, Poole L, Hampshire P, Hall A, Williams K, Walker A, Youds L, Hendry
S, Waugh V, Patrick-Heselton J, Shaw D, Chaudry I, Baldwin J, Drage S, de Gordoa
LO, McAuley D, Mullan B, Bannon L, Quinn V, McNamee L, White G, McFarland M,
Wells B, Cecconi M, Mellinghoff J, Ryan D, Nichol A, Agarwal B, Meale P, James S,
Dhadwal K, Martin D, Walecka A, Ward S, Trinder J, Hagan S, Montgomery J, Leonard
C, Lemon E, Trinick T, Buddhavarapu M, Ward G, Bassford C, Davidson A, McGuigan
K, Benchiheub A, Hickey N, Binning A, Henderson S, Wood J, Burtenshaw AJ, Kelly
D, Martin T, Thrush J, Wollaston J, Graystone S, Nicol G, Sellors G, Young D,
Pearse R, Rowan K, Williams B, McAuley D, Laffey J, Murphy L, Bellingan G,
Harrison D, Gordon A.
Affiliation(s): Author information:
(1)From the Centre for Infection and Immunity, Queen's University of Belfast
(D.F.M., C.M.O.), the Regional Intensive Care Unit (D.F.M., B.M.) and Northern
Ireland Clinical Trials Unit (D.F.M., C. McDowell, C. McNally), Royal Victoria
Hospital, and the Intensive Care Unit, Ulster Hospital (T.J.T.), Belfast, the
Heart of England National Health Service (NHS) Foundation Trust, Birmingham
(G.D.P.), Warwick Medical School Clinical Trials Unit, University of Warwick,
Warwick (G.D.P.), the Intensive Care Unit, Antrim Area Hospital, Antrim (P.J.),
the Critical Care Units, King's Health Partners (King's College Hospital), London
(P.A.H.), and the John Farman Intensive Care Unit, Cambridge University Hospitals
NHS Foundation Trust, Cambridge (A.J.J.) - all in the United Kingdom; the
Department of Anaesthesia, School of Medicine, Health Research Board Galway
Clinical Research Facility, Clinical Sciences Institute, National University of
Ireland, Galway, Ireland (J.G.L.); and the Department of Anesthesia, Centre for
Critical Care Research, Keenan Research Centre for Biomedical Science, St.
Michael's Hospital, University of Toronto, Toronto (J.G.L.).
Publication date & source: 2014, N Engl J Med. , 371(18):1695-703
BACKGROUND: Studies in animals and in vitro and phase 2 studies in humans suggest
that statins may be beneficial in the treatment of the acute respiratory distress
syndrome (ARDS). This study tested the hypothesis that treatment with simvastatin
would improve clinical outcomes in patients with ARDS.
METHODS: In this multicenter, double-blind clinical trial, we randomly assigned
(in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to
receive enteral simvastatin at a dose of 80 mg or placebo once daily for a
maximum of 28 days. The primary outcome was the number of ventilator-free days to
day 28. Secondary outcomes included the number of days free of nonpulmonary organ
failure to day 28, mortality at 28 days, and safety.
RESULTS: The study recruited 540 patients, with 259 patients assigned to
simvastatin and 281 to placebo. The groups were well matched with respect to
demographic and baseline physiological variables. There was no significant
difference between the study groups in the mean (±SD) number of ventilator-free
days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P=0.21) or days free
of nonpulmonary organ failure (19.4±11.1 and 17.8±11.7, respectively; P=0.11) or
in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no
significant difference between the two groups in the incidence of serious adverse
events related to the study drug.
CONCLUSIONS: Simvastatin therapy, although safe and associated with minimal
adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded
by the U.K. National Institute for Health Research Efficacy and Mechanism
Evaluation Programme and others; HARP-2 Current Controlled Trials number,
ISRCTN88244364.).
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