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Simvastatin in Acute Respiratory Distress Syndrome

Journal: New England Journal of Medicine

Manuscript ID: 14-03285.R2

Article Type: Rapid Review

Date Submitted by the Author: n/a

Complete List of Authors: McAuley, Daniel; The Queen's University of Belfast, Centre for Infection and Immunity Laffey, John; National University of Ireland, Galway, School of Medicine O'Kane, Cecilia; Queen's University of Belfast, Centre of Infection and Immunity Perkins, Gavin; Heart of England NHS Foundation Trust, Academic Dept of Critical Care Mullan, Brian; Royal Victoria Hospital, Regional Intensive Care Dept Trinder, John; The Ulster Hospital, Intensive Care Dept Johnston, Paul; Antrim Area Hospital, Intensive Care Unit

Hopkins, Philip; Kings College Hospital, Surgical Critical Care Unit Johnston, Andrew; Addenbrooke's Hospital, John Farman Intensive Care Unit McDowell, Cliona; Northern Ireland Clinical Trials Unit, McNally, Christine; Northern Ireland Clinical Trials Unit,

Abstract:

Background: There are in vitro, animal and phase 2 studies suggesting that statins may be beneficial in 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 multicentre, allocation concealed, double-blind clinical trial, patients with an onset of ARDS within the previous 48 hours were randomized in a 1:1 ratio to receive enteral simvastatin 80mg 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 number of non-pulmonary organ failure free days to day 28, mortality at 28 days and safety. Results: The study recruited 540 patients with 259 patients allocated to simvastatin and 281 patients to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between study groups in mean (± SD) ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P = 0.21), non-pulmonary organ failure free days (19.4±11.1 with simvastatin and 17.8±11.7 with placebo, P = 0.11) or in 28-day mortality

(22.0% with simvastatin and 26.8% with placebo, P = 0.23). There was no difference in the incidence of severe adverse events between the groups. Conclusions: Simvastatin therapy, while safe and with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the UK National Institute for Health Research Efficacy and

Confidential: Destroy when review is complete.

Submitted to the New England Journal of Medicine


Mechanism Evaluation Programme and others; Current Controlled Trials number, ISRCTN88244364.)

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Simvastatin in Acute Respiratory Distress Syndrome

Prof Daniel F McAuley MD1,2,3*

, Prof John G Laffey MD4,5

, Dr Cecilia M O’Kane PhD1,

Prof Gavin D Perkins MD6,7

, Dr Brian Mullan MB2, Dr T John Trinder MB

8, Dr Paul

Johnston MB9, Dr Philip A Hopkins PhD

10, Dr Andrew J Johnston MD

11, Cliona

McDowell MSc3, Christine McNally BA

3, and the HARP-2 investigators* on behalf of the

Irish Critical Care Trials Group.

1 Centre for Infection and Immunity, Queen's University of Belfast, Belfast BT9 7AE,

UK

2 Regional Intensive Care Unit, Royal Victoria Hospital, Belfast BT12 6BA, UK

3 Northern Ireland Clinical Trials Unit, Royal Victoria Hospital, Belfast BT12 6BA, UK

4 Anaesthesia, School of Medicine, HRB Galway Clinical Research Facility, Clinical

Sciences Institute, National University of Ireland, Galway, Ireland

5 Department of Anesthesia, Centre for Critical Care Research, Keenan Research Centre

for Biomedical Science, St. Michael's Hospital, University of Toronto, Canada.

6 Heart of England NHS Foundation Trust, Bordesley Green East, Birmingham B9 5SS,

UK

7. Warwick Medical School Clinical Trials Unit, University of Warwick, Warwick CV4

7AL, UK

8. Intensive Care Unit, The Ulster Hospital, Upper Newtownards Road, Belfast BT16

1RH, UK

9 Intensive Care Unit, Antrim Area Hospital, Antrim BT41 2RL, UK

10 Critical Care Units, King's Health Partners (King's College Hospital), London SE5

9RS, UK

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11 John Farman Intensive Care Unit, Cambridge University Hospitals NHS Foundation

Trust, Cambridge CB2 0QQ, UK

* HARP-2 investigators are listed in the Supplementary Appendix, available at NEJM.org.

*Corresponding author

Professor Danny McAuley

Centre for Infection and Immunity, Queen's University of Belfast

Health Sciences Building, 97 Lisburn Road

Belfast, BT9 7AE

UK

Telephone: 02890 972144

Fax: 02890 972671

Email: [email protected]

Source of funding: This study was funded by the UK National Institute for Health

Research, Efficacy and Mechanism Evaluation (EME) programme (08/99/08). This study

was also funded in Ireland by the Health Research Board (HRA_POR-2010-131). The HSC

R&D Division, Public Health Agency in Northern Ireland, the Intensive Care Society of

Ireland and REVIVE provided additional funding.

Word count (excluding abstract, references and legends): 2325

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Abstract

Background: There are in vitro, animal and phase 2 studies suggesting that statins may be

beneficial in 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 multicentre, allocation concealed, double-blind clinical trial, patients with

an onset of ARDS within the previous 48 hours were randomized in a 1:1 ratio to receive

enteral simvastatin 80mg 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

number of non-pulmonary organ failure free days to day 28, mortality at 28 days and

safety.

Results: The study recruited 540 patients with 259 patients allocated to simvastatin and 281

patients to placebo. The groups were well matched with respect to demographic and

baseline physiological variables. There was no significant difference between study groups

in mean (± SD) ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo,

P = 0.21), non-pulmonary organ failure free days (19.4±11.1 with simvastatin and

17.8±11.7 with placebo, P = 0.11) or in 28-day mortality (22.0% with simvastatin and

26.8% with placebo, P = 0.23). There was no difference in the incidence of severe adverse

events between the groups.

Conclusions: Simvastatin therapy, while safe and with minimal adverse effects, did not

improve clinical outcomes in patients with ARDS.

(Funded by the UK National Institute for Health Research Efficacy and Mechanism

Evaluation Programme and others; Current Controlled Trials number, ISRCTN88244364.)

(Abstract 249 words)

Key Words: simvastatin, acute respiratory distress syndrome

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Background

The acute respiratory distress syndrome (ARDS) is a common devastating clinical

syndrome characterized by life-threatening respiratory failure requiring mechanical

ventilation and multiple organ failure. ARDS is characterized by an uncontrolled

inflammatory response which results in alveolar damage with exudation of protein rich

pulmonary oedema fluid in the alveolar space1. Hydroxyl-methylglutaryl coenzyme A

reductase inhibition with statins has been shown to modify a number of the underlying

mechanisms implicated in the development of ARDS2. Statins decrease inflammation and

histological evidence of lung injury in murine models of ARDS3. Simvastatin reduced

pulmonary and systemic inflammatory responses in a human model of ARDS induced by

LPS inhalation4. In addition in a small single centre, randomized, placebo-controlled study

simvastatin improved non-pulmonary organ dysfunction and was safe5. That phase 2 study

was not designed or powered to show an effect of simvastatin on clinical outcomes. The

aim of this trial was to test the hypothesis that treatment with enteral simvastatin 80mg

would improve clinical outcomes in patients with ARDS irrespective of etiology.

Study design

Patients were recruited from adult general intensive care units (ICUs) in 40 hospitals in the

United Kingdom and Ireland (see the Supplementary Appendix, available with the full text

of this article at NEJM.org). The study was approved by a research ethics committee

(10/NIR02/36) and research governance departments at each site in the UK and by the

institutional Research Ethics Committee at each site in Ireland. The Northern Ireland

Clinical Trials Unit coordinated the overall trial, with support from the HRB Galway

Clinical Research Facility for centres in Ireland. Patients or their representatives provided

written informed consent. Simvastatin was purchased for use in the study.

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The study design has been published in detail previously6 and the study protocol and

statistical analysis plan are available at NEJM.org.

Patients

Patients were eligible if they were intubated and mechanically ventilated and had a partial

pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FIO2) ratio of

300 mmHg or less, if bilateral pulmonary infiltrates consistent with pulmonary edema were

present on chest radiograph, and if there was no evidence of left atrial hypertension7.

Exclusion criteria are listed in Fig. 1 and in full in the protocol at NEJM.org. The study was

amended to permit enrolment of patients receiving macrolides and for the level of alanine

aminotransferase and/or aspartate aminotransferase for eligibility to be increased from more

than 5 times to 8 times the upper limit of the normal range.

Study medication

Patients were randomized in a 1:1 ratio using an automated centralised 24-hour

randomization service. Randomization was by permuted block stratified by site and by

vasopressor requirement.

Patients received once daily simvastatin 80mg or identical placebo tablets enterally for up

to 28 days. The first dose of study drug was administered as soon as possible, ideally within

4 hours of randomization, and subsequent doses were given each morning starting on the

following calendar day.

Study drug was continued until day 28, discharge from critical care, death or

discontinuation of active medical treatment, development of a clinical condition requiring

immediate treatment with a statin or withdrawal of the patient from the study. The study

drug was stopped on safety grounds if the attending clinician determined that this was

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required, if the levels of creatine kinase were more than 10 times the upper limit of the

normal range or if the levels of alanine aminotransferase and/or aspartate aminotransferase

were more than 8 times the upper limit of the normal range.

Data collection and procedures

At enrolment, the patients’ demographic characteristics, ventilatory and physiological

variables and admission acute physiology and chronic health evaluation II (APACHE II)

scores were recorded. The cause of ARDS was identified by the treating clinician. For each

day in the ICU, ventilatory and physiological variables as well as data on organ support

based on the United Kingdom’s critical care minimum data set8 were recorded. Vital status

at 28 days was collected but cause of death was not recorded.

Participating ICUs were encouraged to use low tidal volume ventilation at 6 to 8 ml per

kilogram of predicted body weight and to maintain plateau pressure less than 30 cmH2O9,

but no specific ventilator management scheme was promulgated. All other treatment was

determined by the patients’ physicians.

Outcome measures

The primary outcome measure was ventilator-free days (VFDs) to day 28 defined as the

number of days from the time of initiating unassisted breathing, to day 28 after

randomization6. A detailed definition of VFDs is provided in the study protocol available at

NEJM.org. Secondary outcomes included change in oxygenation index (OI) and sequential

organ failure assessment (SOFA) score10 up to day 28, number of non-pulmonary organ

failure free days (OFFDs) to day 28, all cause mortality 28 days post randomization,

mortality at discharge from critical care and from hospital, and safety.

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Additional secondary outcomes are listed in the protocol. Plasma C-reactive protein (CRP)

was measured by immunoturbidimetric assay (Randox Testing Services, UK) in blood

obtained at baseline, day 3 and 7.

Statistical analysis

Sample size assumptions were based on previously published data5,9

. Assuming a mean

(SD) for VFDs of 12.7 (10.6) days, a sample size of 524 subjects would need to be enrolled

to have 80% power at a two-tailed significance level of 0.05 to detect a mean difference of

2.6 VFDs. Data from the PAC-Man trial were used to estimate a dropout rate of 3%11 and

therefore the study required a total of 540 patients.

Analyses were on an intention-to-treat basis. As VFDs and non-pulmonary OFFDs are

known to have a bimodal distribution, the groups were initially analysed by t-test with

difference in means and 95% confidence intervals (CI) presented. A secondary analysis of

these outcome measures involving a bootstrapped t-test was also conducted to support the

findings of the t-tests as detailed in the statistical analysis plan available at NEJM.org. For

binary outcome measures, risk ratios and associated 95% CI were calculated. Time-to-event

data are presented using Kaplan-Meier plots. The hazard ratios (HR) were calculated and

the log rank chi-square test used to compare the survival function of treatment arms. All

HRs are presented with a 2-sided 95% CI. All P values are 2-sided. To assess whether

treatment was more or less effective in pre-defined subgroups, analyses were undertaken to

analyse whether the treatment effect was modified by age, vasopressor requirement,

presence of sepsis and baseline CRP. Subgroup analyses used a statistical test for

interaction and are reported using 99% CI.

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Results

Participants

Patients were recruited from 21st December 2010 until 13th March 2014. Of the 5926

patients who were assessed for eligibility, 540 (9%) underwent randomization. Four

patients who did not fulfil the eligibility criteria were randomized in each group and are

included in the analysis. Five patients allocated to simvastatin and 3 patients in the placebo

group did not receive study drug. One patient in the simvastatin group was lost to follow-

up. No data on the primary outcome was available in 1 patient in the simvastatin group and

2 patients in the placebo group (Fig. 1).

The baseline characteristics of the patients at randomization were similar in the two study

groups except for a small but statistically significant lower PaO2/FIO2 ratio in the

simvastatin group (Table 1). The main causes of ARDS were pneumonia and sepsis. There

was no significant difference in tidal volume at day 3; mean difference (95% CI) was 0.1 (-

0.6 to 0.7) ml/kg predicted body weight (P = 0.89).

Patients received study drug for a mean (±SD) of 10.2 ± 7.1 days in the simvastatin group

and 11 ± 7.9 days in the placebo group (P = 0.23). The commonest reasons for

discontinuation of study drug were discharge from critical care, death and a study drug

related adverse event. Five patients allocated to simvastatin and 3 patients allocated to

placebo received treatment with non-trial statins (Table S1 in the Supplementary

Appendix).

Outcomes

The number of ventilator-free days was not significantly different between the study groups

(12.6±9.9 with simvastatin and 11.5±10.4 with placebo, mean difference (95% CI) of 1.1 (-

0.6 to 2.8); P = 0.21). There was no significant difference in the number of ventilator-free

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days after adjusting for the baseline PaO2/FIO2 ratio (mean difference (95% CI) of 1.4 (-0.3

to 3.2); P = 0.10).

There were no significant differences in the change in oxygenation index (Tables S2 and S3

in the Supplementary Appendix) or SOFA score from baseline between the groups (Table

S2 in the Supplementary Appendix). There was no significant difference in the number of

non-pulmonary organ failure free days or 28-day mortality. Mortality at critical care

discharge or hospital discharge was also not significantly different (Table 2). For survivors

only, the duration of ICU stay was 13.9±14.4 days in the simvastatin group and 14.4±13.3

days in the placebo group (mean difference (95% CI) of -0.5 (-3.2 to 2.2); P = 0.71); the

duration of hospital stay was 37.7±64.5 days and 35.4±31.1 days, respectively (mean

difference (95% CI) of 2.3 (-8.0 to 12.6); P = 0.66). There was no significant difference in

the probability of breathing without assistance to day 28 or survival (Fig. 2).

Subgroup analyses did not suggest that the effects of simvastatin were modified by any of

the variables investigated. There was no statistically significant interaction between

treatment and age (P = 0.62), vasopressor requirement (P = 0.17), presence of sepsis (P =

0.50) and baseline C-reactive protein (CRP) (P = 0.77) (Table S4 in the Supplementary

Appendix).

There were no differences in plasma CRP between the simvastatin and placebo groups at

baseline, at day 3 or day 7 or in the change in the CRP from baseline (Tables S5 and S6 in

the Supplementary Appendix).

Overall adverse events related to study drug were significantly more common in the

simvastatin group. The majority were related to elevated creatine kinase and hepatic

transaminases. Serious adverse events (SAEs) (other than those reported as trial outcomes

e.g. death) were similar in both groups (Table S7 in the Supplementary Appendix). There

was no difference in the proportion of patients with non-pulmonary organ dysfunction as

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measured by a SOFA score less than 2, by organ, between the groups (Table S8 in the

Supplementary Appendix).

Discussion

In this large, multicentre, double-blind, randomized, placebo-controlled clinical trial in

patients with ARDS, simvastatin did not improve clinical outcomes. Simvastatin was

associated with an increase in adverse events; however there was no increase in serious

adverse events. The recent SAILS study in patients with sepsis-induced ARDS found

rosuvastatin did not improve clinical outcomes and was associated with fewer days free of

renal and hepatic failure12 The patient population in this study was not limited to sepsis-

induced ARDS, and therefore taken together these data do not support the routine use of

statins in ARDS, regardless of aetiology.

We used simvastatin 80mg based on our previous human data4,5

where simvastatin

improved surrogate outcomes and biological mechanisms implicated in ARDS. The data

from this study and SAILS demonstrate that neither lipophilic (simvastatin) nor hydrophilic

(rosuvatatin) statins are effective in ARDS. The high dose (80mg) used in this trial was

selected based on our pilot data5 as well as pre-clinical data

3 and observational studies

13,14

which supported using a higher dose. While we did not measure simvastatin concentrations,

it is likely that an adequate simvastatin concentration was achieved for several reasons.

Prior studies in the critically ill indicate that simvastatin 80mg daily produces systemic

drug concentrations that are in the high therapeutic range15. Furthermore patients received

simvastatin for a mean of 10 days. Finally the increased incidence of expected statin related

adverse events suggest that sufficient simvastatin concentrations were achieved. The lack of

an effect on plasma CRP suggests that statins are unable to modulate inflammation

sufficiently to translate into a beneficial clinical effect in ARDS. It is possible that

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HMGCo-A reductase is already significantly inhibited as reflected by the low cholesterol

levels seen in the critically ill16.

Although there was a higher incidence of adverse events related to simvastatin, the number

of serious adverse events were similar in both groups. The finding that the proportion of

patients with no organ dysfunction as measured by SOFA score over the course of the study

was similar in both groups is reassuring. The absence of serious harm with simvastatin in

this population provides reassurance in regard to the safety of statins in patients with ARDS

used for other proven indications.

We recruited a heterogeneous cohort of patients with ARDS due to any etiology to ensure

that our findings would be generalisable. Recent data have suggested that it may be

possible to identify specific phenotypes within ARDS17. Future studies may identify an

ARDS subpopulation which might be more responsive to simvastatin.

Although we recommended best practice for ARDS including lung protective ventilation,

we did not measure details of clinical management. At randomization, the tidal volume was

8.1ml/kg predicted body weight and it is possible that this level of tidal volume may have

confounded the potential effects of simvastatin. However this is unlikely given the similar

absence of benefit for rosuvastatin in the SAILS study where the mean tidal volume was

6.6-6.8ml/kg predicted body weight. Our data for tidal volume and plateau pressure are

consistent with those seen in other clinical trials in critical care where ventilation is not

strictly protocolized18.

Despite promising findings for statins in ARDS in early phase clinical trials, these have not

been translated into improvements in patient centred outcomes in large clinical trials.

Another recent randomized controlled trial in patients with ventilator associated pneumonia

found simvastatin did not improve clinical outcomes19. Data on efficacy based on surrogate

outcomes must be considered with caution given lack of clear correlation between surrogate

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and patient centred outcomes. More work is required to identify surrogates outcomes which

more closely track patient outcomes.

In conclusion, our study showed that simvastatin, while safe and generally well tolerated,

did not increase the number of ventilator free days or improve other clinical outcomes in

patients with ARDS. These results do not support the use of simvastatin in the management

of ARDS.

Author contributions

DM conceived the study. DM, JGL and CMO designed and obtained the funding for the

study. DM, JGL, CMD and CMN managed the undertaking of the trial with the clinical

trials unit. All authors made a substantial contribution to the protocol development. DFM,

JGL, GDP, BM, JT, PJ, PAH and AJJ contributed substantially to patient recruitment and

data collection. CMD was the study statistician and DM, JGL and CMO interpreted the

data. DM wrote the first draft of the manuscript and all authors have reviewed and have

approved this final version of the manuscript.

Acknowledgements

This project was supported by the Efficacy and Mechanism Evaluation (EME) Programme,

an MRC and NIHR partnership (08/99/08). The EME Programme is funded by the MRC

and NIHR, with contributions from the CSO in Scotland and NISCHR in Wales and the

HSC R&D Division, Public Health Agency in Northern Ireland. The views expressed in

this publication are those of the authors and not necessarily those of the MRC, NHS, NIHR

or the Department of Health. This study was also funded in Ireland by a Health Research

Award from the Health Research Board, Dublin, Ireland (HRA_POR-2010-131). The HSC

R&D Division, Public Health Agency in Northern Ireland and the Intensive Care Society of

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Ireland and REVIVE provided additional funding. DFM and GDP are Directors of

Research for the Intensive Care Foundation and the support of the UK Intensive Care

Foundation is gratefully acknowledged. We thank all patients and their legal representatives

who participated in the trial, all the research nurses and the pharmacists in all participating

centres for their help, and medical and nursing staff in participating centres who cared for

patients and collected data. We thank Regina Verghis, Evie Gardner and all the staff of the

Northern Ireland Clinical Trials Unit for their support in delivering this trial. We thank

Michael Faherty, Emma Deenihan, Veronica McInerney and Lisa Daly from the HRB

Galway Clinical Research Facility, Galway, Ireland, for their help in conducting the study

in Ireland. We are grateful for the support of Margaret McFarland and staff at Victoria

Pharmaceuticals (Belfast, UK) for management of the study drug. We are grateful for the

support of the Intensive Care National Audit and Research Centre (ICNARC) for providing

APACHE II data for sites that participate in ICNARC’s Case Mix Programme. The authors

acknowledge the support of the Northern Ireland Clinical Research Network and the

National Institute for Health Research Clinical Research Network.

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Table 1. Baseline characteristics of the patients.*

Simvastatin

(N = 259)

Placebo

(N = 280)

Age - yr 53.2 ±16.1 54.4 ± 16.7

Male sex – no. (%) 137 (52.9) 170 (60.7)

Sepsis – no. (%) 189 (73.0) 218 (77.9)

Etiology of ARDS#

Smoke/toxin inhalation 1 (0.3) 2 (0.5)

Gastric content aspiration 21 (6.0) 29 (7.7)

Thoracic trauma 22 (6.3) 10 (2.7)

Pneumonia 161 (46.0) 154 (41.1)

Sepsis 106 (30.3) 118 (31.5)

Pancreatitis 5 (1.4) 17 (4.5)

Non-thoracic trauma 4 (1.1) 8 (2.1)

Other 30 (8.6) 37 (9.9)

APACHE II score† 19.4±6.9 18.3± 6.2

SOFA score‡ 8.5±3.2 8.8±2.9

Vasopressor dependent – no. (%) 169 (65.2) 187 (66.8)

Lowest mean arterial pressure -

mmHg

65.4±9.3 64.9± 8.4

Inspiratory plateau pressure – cm of

water

23.6± 6.07 23.6± 6.03

Tidal Volume - ml/kg of predicted 8.1± 2.8 8.1± 2.6

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body weight§

PaO2/FiO2 ratio¶ - mm Hg 123.0±54.8 132.4±55.4

Oxygenation index - cm of

water/mm Hg

15.0±11.6 14.9±11.9

Alanine aminotransferase - U/liter 45.5±47.1 45.8±43.2

Aspartate aminotransferase - U/liter 59.9±49.4 65.3±63.9

Creatine kinase - U/liter 327.2±499.3 298.3±487.7

* Plus–minus values are means ±SD. There was no significant difference between groups

except PaO2/FIO2.

ARDS denotes acute respiratory distress syndrome, FiO2 fraction of inspired oxygen, and

PaO2 partial pressure of arterial oxygen (mmHg).

# Patients can have more than one cause for ARDS identified.

† Scores on the Acute Physiology and Chronic Health Evaluation (APACHE) II scale range

from 0 to 71, with higher scores indicating more severe disease.

‡ Scores on the Serial Organ Failure Assessment scale range from 0 to 24, with higher

scores indicating more severe disease.

§ Predicted body weight was calculated as 2.3 kg for each inch of height above 60 in. added

to 50 kg for men or 45.5 kg for women.

¶ P=0.049

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Table 2. Main Clinical Outcome variables.*

Simvastatin

Placebo

Difference or

Risk Ratio

(95% CI)

p-value

Ventilator-free days

to 28 days post

randomization¶

n 258 279

12.6±9.9

(11.3 to 13.8)

11.5±10.4

(10.2 to 12.7)

1.1 (-0.6 to 2.8)‡

1.1 (-0.7 to 2.8)‡

0.21

0.22†

Non pulmonary organ

failure-free days to 28

days post

randomization #

n 257 279

19.4±11.1

(18.0 to 20.8)

17.8±11.7

(16.4 to 19.2)

1.6 (-0.4 to 3.5)‡

1.6 (-0.3 to 3.5)‡

0.11

0.10†

All-cause mortality 28 days post

randomization – no./total no. (%)

and 95% CI

57/259 (22.0)

(17.0 to 27.1)

75/280 (26.8)

(21.6 to 32.0)

0.8 (0.6 to 1.1)§ 0.23

Death before discharge from

critical care – no./total no. (%)

and 95% CI

56/259 (21.6)

(16.6 to 26.6)

70/280 (25.0)

(19.9 to 30.1)

0.9 (0.6 to 1.2)§ 0.36

Death before discharge from

hospital – no./total no. (%)

and 95% CI

67/259 (25.9)

(20.5 to 31.2)

90/280 (32.1)

(26.7 to 37.6)

0.8 (0.6 to 1.1)§ 0.13

* Plus–minus values are means ±SD with 95% CI. CI denotes confidence interval.

‡ Difference and 95% CI.

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¶ Ventilator-free days are defined in the study protocol. Patients who died before day 28

were assigned zero ventilator free days.

† The results from the bootstrapped t-test also presented.

# Non pulmonary organ failure-free days are defined in the study protocol. Patients who

died before day 28 were assigned zero non pulmonary organ failure-free days. Organs were

considered failure-free after patients were discharged from the critical care unit.

§ Risk Ratio and 95% CI.

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Figure legends

Figure 1. Screening, randomization, and follow-up of the study participants.

There may have been more than one reason for exclusion of a patient. ARDS denotes Acute

Respiratory Distress Syndrome and CK creatine kinase.

Figure 2. Probability of survival and breathing without assistance from randomization to

day 28 according to whether patients received simvastatin or placebo. Alive, Simvastatin

denoted in black, Alive, Placebo in red, Unassisted breathing, Simvastatin in blue and

Unassisted breathing, Placebo in green. The numbers of patients at risk in each group are

indicated in the corresponding colour.

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Figure 1.

5926 were assessed for eligibility

258 were included in the analysis of the primary outcome

1 patient was lost to follow-‐up

1 patient was lost to follow-‐up (day 9)

259 were allocated to simvastatin 254 received simvastatin 5 did not receive simvastatin

2 were on a statin 1 had elevated transaminases 2 unable to insert nasogastric tube

0 patients were lost to follow-‐up

281 were allocated to placebo 278 received placebo 3 did not receive placebo

1 had elevated CK 1 consent was withdrawn 1 other reason

279 were included in the analysis of the primary outcome

2 withdrawal of consent

540 were randomized

5386 were excluded

9 were <16 years of age 312 were not intubated/ventilated 719 were more than 48 hours from onset of ARDS 15 were known to be pregnant 194 had elevated CK 342 had elevated transaminases 340 had interaction with concomitant drug 235 had severe renal impairment and were not receiving renal replacement therapy 223 had severe liver disease (Child-‐Pugh score > 12) 1803 had received statins within the previous two weeks 75 required a statin for a proven indication 117 had a contraindication to enteral drug administration 103 were enrolled in another drug trial 309 treatment withdrawal imminent 197 declined to consent 836 had other reason

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Number at risk

Survival

Simvastatin 259 238 217 208 202

Placebo 280 250 231 220 205

Unassisted breathing

Simvastatin 258 166 87 43 19

Placebo 279 178 102 60 33

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