Statin therapy for acute respiratory distress syndrome: an ...



Intensive Care Medicine: Supplementary appendixStatin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trialsMyura Nagendran1Daniel F McAuley2Peter S Kruger3Laurent Papazian4Jonathon D Truwit5John G Laffey6B Taylor Thompson7Mike Clarke2Anthony C Gordon1Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, UKSchool of Medicine, Dentistry and Biomedical Sciences, Queen’s University of Belfast, UKPrincess Alexandra Hospital, Metro South Health, Woolloongabba,?Queensland, Australia and School of Medicine, University of Queensland, Australia.Medical Intensive Care Unit, North Hospital, Aix-Marseille University, FrancePulmonary and Critical Care Medicine, Froedtert and Medical College of Wisconsin, Milwaukee, WI, USADepartment of Anesthesia, St Michael’s Hospital, Toronto, CanadaDivision of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston MA, USACorresponding author: Prof. Anthony Gordon – anthony.gordon@imperial.ac.ukSupplementary methodsInclusion and exclusion criteria for individual trials – taken directly from trial manuscriptsHARP-1PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DcmFpZzwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [1]Mechanically ventilated patients at the Regional Intensive Care Unit in the Royal Victoria Hospital, Belfast, Northern Ireland were eligible for inclusion into the study within 48 hours of the diagnosis of ALI and ARDS. Exclusion criteria included creatine kinase (CK) > 10 times upper limit normal range, liver transaminases > 3 times upper limit normal range, patients with severe renal impairment (calculated creatinine clearance < 30 ml/min) not receiving renal replacement therapy, patients with severe liver disease (Child's Pugh score > 11), known lactose intolerance, current treatment with any lipid lowering agent including statins, contraindication to enteral drug administration; age < 18 years; pregnancy; participation in a clinical trial with an investigational medicinal product within 30 days, unlikely to survive beyond 48 hours, and declined consent.Kruger et al. 2011PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcnVnZXI8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [2]The inclusion criteria were (1) proven or suspected infection for which antibiotic therapy had been commenced; (2) the presence of at least two of the four criteria of the systemic inflammatory response syndrome (SIRS); and (3) the patient had to be on preexisting statin therapy and the treating physician prepared to either continue or discontinue this therapy.Exclusion criteria included pregnancy; acute liver failure; chronic liver disease (Childs B or C); not expected to survive 24 hours; already enrolled in another clinical trial; rhabdomyolysis or myopathy of any cause; acute coronary syndrome or an acute stroke; and patients in whom systemic manifestations of inflammation (two or more SIRS criteria) had abated for more than 36 hours. Patients in whom enteral intake was clearly not possible within 72 hours of hospitalization, thus precluding study drug administration, and patients who had missed more than two doses of their usual statin before randomization were also excluded.STATInSPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LcnVnZXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [3]Patients were eligible for enrolment if they were critically ill; aged between 18 and 90 years; had strongly suspected or proved infection; fulfilled three or more of the features of systemic inflammatory response syndrome within the 48 hours before randomization; and had an organ dysfunction of less than 24 hours duration.Patients were excluded from the study if they were moribund or not expected to survive 28 days because of an underlying irreversible medical condition; were pregnant or breast feeding; had a known intolerance to statins or were unable to have enteral administration of study drug; had severe liver disease (acute liver failure, chronic liver disease Child-Pugh classification C); had a serum alanine amino transferase (ALT) level greater than five times the normal value or a serum creatinine kinase level (CK) level greater than 10 times the upper limit of normal; had commenced statin therapy less than 2 weeks before hospital admission or had statin stopped for more than 72 hours before the development of sepsis; or if informed consent could not be obtained.STATIN-VAPPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXBhemlhbjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

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ZE5vdGU+

ADDIN EN.CITE.DATA [4]Consecutive adults who had received mechanical ventilation in the ICU for at least 2 days were eligible if they had suspected VAP defined as a modified Clinical Pulmonary Infection Score (CPIS) of at least 5 and if they underwent quantitative bacteriological cultures of bronchoalveolar lavage (BAL) fluid, a protected telescopic catheter (PTC), or an endotracheal aspirate. The modified CPIS16 is based on body temperature, blood leukocyte count, amount and appearance of tracheal secretions, ratio of Pao2 to fraction of inspired oxygen, acute respiratory distress syndrome (ARDS), and infiltrates on chest radiography. The total can range from 1 to 10 points. Patients were included only for the first episode of suspected VAP. Noninclusion criteria were statin therapy at intubation, previous VAP episode during the same hospitalization, known pregnancy, immunodepression with bone marrow aplasia, imminent death (Simplified Acute Physiology Score II of 75 or greater, calculated over the last 6 hours), treatment-limitation decisions, nothing-by-mouth order and no nasogastric tube, continuous gastric aspiration, known chronic intestinal malabsorption, known simvastatin hypersensitivity, acute hepatic failure, use of CYP3A4 inhibitors or cyclosporine, creatine kinase level greater than 5 times the upper limit of normal, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels greater than 3 times the upper limit of normal, and enrollment in another trial within the previous 30 days.HARP-2PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0F1bGV5PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA [5]Patients were eligible if they were intubated and mechanically ventilated and were within 48 hours after the onset of ARDS as defined by a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) of 300 mm Hg or less, if bilateral pulmonary infiltrates consistent with pulmonary edema were present on chest radiography, and if there was no evidence of left atrial hypertension.The main exclusion criteria are listed in Figure 1SAILSPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcnV3aXQ8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [6]Patients were eligible for enrollment if they were receiving positive-pressure mechanical ventilation through an endotracheal tube, had a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of 300 or less, and had bilateral infiltrates on chest radiography that were consistent with pulmonary edema, without evidence of left atrial hypertension.25 These criteria had been met during a single 24-hour period. Additional inclusion criteria were a known or suspected infection and either of the following criteria for a systemic inflammatory response: a white-cell count of more than 12,000 per cubic millimeter or less than 4000 per cubic millimeter or a differential count with more than 10% band forms, or a core body temperature of more than 38°C or less than 36°C.26Reasons for exclusion are listed in the Supplementary Appendix. Major exclusion criteria were the presence of ARDS for more than 48 hours; chronic conditions that could adversely affect survival, impair weaning from the ventilator, or compromise adherence to the protocol; serum levels of creatine kinase, aspartate aminotransferase, or alanine aminotransferase of more than five times the upper limit of the normal range; ingestion of a statin (on an inpatient or outpatient basis) in the 48 hours before randomization; and an inability to obtain consent.A-priori defined subgroups.Shock versus no shockShock defined as vasopressor requirement at baselinePrior statin use versus no prior usePrior use defined as any statin use preceding randomisationAetiology of acute lung injury (sepsis versus no sepsis)Sepsis defined as per Surviving Sepsis Guidelines 2012Low CRP versus high CRPHigh CRP defined as CRP greater than the median baseline CRP value of the combined individual patient datasetType of statin (hydrophilic versus lipophilic)Hydrophilic include pravastatin and rosuvastatinLipophilic include simvastatin, atorvastatin, fluvastatinLow versus high dose of statinLow dose statin defined as half the maximum dose recommended by the British National Formulary (BNF) or lowerSimvastatin low dose: ≤ 40mgAtorvastatin low dose: ≤ 40mgRosuvastatin low dose: ≤ 20mgPravastatin low dose: ≤ 20mgFluvastatin low dose: ≤ 40mgP/F ratioCategorised based on the Berlin ARDS definition:Mild ARDS (200 < PaO2/FiO2 ≤ 300 mmHg)Moderate ARDS (100<PaO2/FiO2 ≤ 200 mmHg)Severe ARDS (PaO2/FiO2 <100 mmHg)Low versus high risk of bias trials:Low risk trial defined as being at low risk of bias in all assessed domainsHigh risk is defined as not being at low risk of biasFigure S1 Flow of records through the selection processTable S1. Trial CharacteristicsLead authorTrial nameYearSample sizeStatinDoseOnly ARDS patients?Craig et al.HARP-1201160Simvastatin80mgYesKruger et al.-2011150Atorvastatin20mgNoKruger et al.STATInS2013250Atorvastatin20mgNoPapazian et al. STATIN-VAP2013300Simvastatin60mgNoMcAuley et al.HARP-22014540Simvastatin80mgYesTruwit et al.SAILS2014745Rosuvastatin20mg (after 40mg loading)YesTable S2. Risk of bias in included studiesTrialYearSequence generationAllocation concealmentBlinding of participants and healthcare providersBlinding of outcome assessorsIncomplete outcome dataSelective reportingOther sources of biasHARP-12011LowLowLowLowLowLowLowKruger et al.2011LowLowLowLowLowLowLowSTATInS2013LowLowLowLowLowLowLowSTATIN-VAP 2013LowLowLowLowLowLowLowHARP-22014LowLowLowLowLowLowLowSAILS2014LowLowLowLowLowLowLowTable S3. Two stage analyses of primary and secondary outcomesTWO STAGE, FIXED EFFECT, PRIMARY OUTCOMESNo. of studiesMeasureEffect sizeLower 95% CIUpper 95% CIp value28 day mortality5RR1.0290.8621.2280.260Ventilator free days4MD0.337-0.6821.3560.721Serious Adverse Events5RR1.1370.8431.5330.410TWO STAGE, RANDOM EFFECT, PRIMARY OUTCOMES28 day mortality5RR1.0410.8301.3070.727Ventilator free days4MD0.337-0.6821.3560.721Serious Adverse Events5RR1.1360.8401.5380.407TWO STAGE, FIXED EFFECT, SECONDARY OUTCOMESVentilation duration2MD-1.042-6.0153.9320.882Requirement for Renal Replacement Therapy3RR0.9740.7971.1910.799ICU free days to day 285MD0.093-0.7510.9380.90190 day mortality3RR0.9730.8231.1510.752ICU length of stay5MD-0.583-1.8050.6380.752Hospital length of stay4MD-0.634-2.5931.3240.443Adverse events5RR1.3961.0681.8250.015TWO STAGE, RANDOM EFFECT, SECONDARY OUTCOMESVentilation duration2MD-1.042-6.0153.9320.882Requirement for Renal Replacement Therapy3RR0.9680.7661.2220.782ICU free days to day 285MD0.093-0.7510.9380.90190 day mortality3RR0.9700.8081.1640.742ICU length of stay5MD-0.583-1.8050.6380.752Hospital length of stay4MD-0.634-2.5931.3240.443Adverse events5RR1.3561.0411.7670.024Abbreviations: CI, confidence interval; ICU, intensive care unit; MD, mean difference (non-standardised); RR, relative risk.Table S4. One stage analyses of primary and secondary outcomesONE STAGE, FIXED EFFECT, PRIMARY OUTCOMESNo. of studiesMeasureEffect sizeLower 95% CIUpper 95% CIp value28 day mortality5OR1.0380.8271.3020.750Ventilator free days4Coefficient0.334-0.6931.3610.523Serious Adverse Events5OR1.1550.8261.6140.401ONE STAGE, RANDOM EFFECT, PRIMARY OUTCOMES28 day mortality5OR1.0380.8271.3020.750Ventilator free days4Coefficient0.334-0.6901.3590.522Serious Adverse Events5OR1.1550.8261.6140.401ONE STAGE, FIXED EFFECT, SECONDARY OUTCOMESVentilation duration2Coefficient-1.311-8.4845.8630.719Requirement for Renal Replacement Therapy3OR0.9670.7471.2510.798ICU free days to day 285Coefficient0.051-0.8190.9210.90890 day mortality3OR0.9630.7641.2150.752ICU length of stay5Coefficient-1.281-2.8980.3370.121Hospital length of stay4Coefficient1.044-2.2054.2930.529Adverse events5OR1.4911.0832.0540.014ONE STAGE, RANDOM EFFECT, SECONDARY OUTCOMESVentilation duration2Coefficient-1.311-8.4045.7820.717Requirement for Renal Replacement Therapy3OR0.9670.7471.2510.798ICU free days to day 285Coefficient0.051-0.8170.9190.90890 day mortality3OR0.9630.7641.2150.752ICU length of stay5Coefficient-1.281-2.8940.3330.120Hospital length of stay4Coefficient1.044-2.1974.2850.528Adverse events5OR1.4911.0832.0540.014Abbreviations: CI, confidence interval; ICU, intensive care unit; OR, odds ratio. Table S5. Sensitivity analysis of primary outcomes with only trials satisfying full ARDS criteria (HARP-1, HARP-2, SAILS).TWO STAGE, FIXED EFFECT, PRIMARY OUTCOMESMeasureEffect sizeLower 95% CIUpper 95% CIp value28 day mortalityRR0.9820.8091.1920.854Ventilator free daysMD0.393-0.7251.5120.528Serious Adverse EventsRR0.9040.6151.3280.607Table S6. One stage single treatment covariate interaction models for 28 day mortalityInteraction coefficientStandard errorp valueAICShockModel A-0.1610.2430.5091816Model B-0.1630.2430.5041822Model C-0.0860.2510.7321823SepsisModel A-0.1770.3660.6281844Model B-0.1830.3670.6181846Model C-0.3460.3910.3761846ARDS severityModel A0.052, -0.2040.280, 0.3410.853, 0.5491800Model B0.092, -0.1570.283, 0.3440.745, 0.6481805Model CNA (cat)NA (cat)NA (cat)NA (cat)CRPModel A-0.0240.2590.9251483Model B-0.0330.2590.8981487Model C-0.1100.2650.6791487Statin doseModel A-0.7900.2320.7331847Model B-0.7900.2320.7331847Model CNA (ts)NA (ts)NA (ts)NA (ts)Statin typeModel A-0.1240.2330.5951847Model B-0.1240.2330.5951847Model CNA (ts)NA (ts)NA (ts)NA (ts)Previous statinModel A-0.129-0.4030.7481155Model B-0.1300.4020.7461158Model C-0.0440.4100.9141158Model A = One stage random effects model with treatment-covariate interaction ADDIN EN.CITE <EndNote><Cite><Author>Turner</Author><Year>2000</Year><RecNum>79</RecNum><DisplayText>[7]</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="eaa2wewzbza298e5rwxx5zfn2x2szz0a52aa" timestamp="1474149272">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Turner, R. M.</author><author>Omar, R. Z.</author><author>Yang, M.</author><author>Goldstein, H.</author><author>Thompson, S. G.</author></authors></contributors><auth-address>MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. rebecca.turner@ctu.mrc.ac.uk</auth-address><titles><title>A multilevel model framework for meta-analysis of clinical trials with binary outcomes</title><secondary-title>Stat Med</secondary-title><alt-title>Statistics in medicine</alt-title></titles><periodical><full-title>Statistics in Medicine</full-title><abbr-1>Stat. Med.</abbr-1><abbr-2>Stat Med</abbr-2></periodical><alt-periodical><full-title>Statistics in Medicine</full-title><abbr-1>Stat. Med.</abbr-1><abbr-2>Stat Med</abbr-2></alt-periodical><pages>3417-32</pages><volume>19</volume><number>24</number><edition>2000/12/21</edition><keywords><keyword>Clinical Trials as Topic/statistics &amp; numerical data</keyword><keyword>Confidence Intervals</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Likelihood Functions</keyword><keyword>Logistic Models</keyword><keyword>*Meta-Analysis as Topic</keyword><keyword>*Models, Statistical</keyword><keyword>Odds Ratio</keyword><keyword>Outcome Assessment (Health Care)</keyword><keyword>Pre-Eclampsia/drug therapy</keyword><keyword>Pregnancy</keyword><keyword>Respiratory Tract Infections/drug therapy</keyword></keywords><dates><year>2000</year><pub-dates><date>Dec 30</date></pub-dates></dates><isbn>0277-6715 (Print)&#xD;0277-6715</isbn><accession-num>11122505</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]. 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ADDIN EN.CITE.DATA [8].Model B = One stage random effects model with treatment-covariate interactionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW1tb25kczwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+

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ADDIN EN.CITE.DATA [9, 10]. This model allows for independent effects of the covariate on risk across trials, known as model 4 in Stewart et al. 2012PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA [8].ABBREVIATIONS: AIC = Akaike information criterion, DNC = Model did not converge, NA (cat) = Model not applicable for categorical covariate, NA (ts) = Model not applicable as subgroup defined by trial Table S7. One stage single treatment covariate interaction models for ventilator free daysInteraction coefficientStandard errorp valueAICShockModel A-1.220-1.220-1.220-1.220Model B-1.1271.0250.27111989Model C-1.3391.0540.20411991SepsisModel A-0.0031.4890.99912046Model B-0.0191.4880.99012049Model C0.1861.5630.90512050ARDS severityModel A-0.654, -1.4261.342, 1.5550.626, 0.35911745Model B-0.706, -1.5211.347, 1.5610.600, 0.33011754Model CNA (cat)NA (cat)NA (cat)NA (cat)CRPModel A-0.6861.1810.5629564Model B-0.6721.1820.5709567Model C-0.5021.1950.6749568Statin doseModel A0.6981.0480.50512048Model B0.6981.0480.50512048Model CNA (ts)NA (ts)NA (ts)NA (ts)Statin typeModel A0.6981.0480.50512048Model B0.6981.0480.50512048Model CNA (ts)NA (ts)NA (ts)NA (ts)Previous statinModel A-0.6221.9900.7557419Model B-0.6011.9910.7637421Model C-0.5941.9960.7667423Model A = One stage random effects model with treatment-covariate interaction ADDIN EN.CITE <EndNote><Cite><Author>Turner</Author><Year>2000</Year><RecNum>79</RecNum><DisplayText>[7]</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="eaa2wewzbza298e5rwxx5zfn2x2szz0a52aa" timestamp="1474149272">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Turner, R. M.</author><author>Omar, R. Z.</author><author>Yang, M.</author><author>Goldstein, H.</author><author>Thompson, S. G.</author></authors></contributors><auth-address>MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. rebecca.turner@ctu.mrc.ac.uk</auth-address><titles><title>A multilevel model framework for meta-analysis of clinical trials with binary outcomes</title><secondary-title>Stat Med</secondary-title><alt-title>Statistics in medicine</alt-title></titles><periodical><full-title>Statistics in Medicine</full-title><abbr-1>Stat. Med.</abbr-1><abbr-2>Stat Med</abbr-2></periodical><alt-periodical><full-title>Statistics in Medicine</full-title><abbr-1>Stat. Med.</abbr-1><abbr-2>Stat Med</abbr-2></alt-periodical><pages>3417-32</pages><volume>19</volume><number>24</number><edition>2000/12/21</edition><keywords><keyword>Clinical Trials as Topic/statistics &amp; numerical data</keyword><keyword>Confidence Intervals</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Likelihood Functions</keyword><keyword>Logistic Models</keyword><keyword>*Meta-Analysis as Topic</keyword><keyword>*Models, Statistical</keyword><keyword>Odds Ratio</keyword><keyword>Outcome Assessment (Health Care)</keyword><keyword>Pre-Eclampsia/drug therapy</keyword><keyword>Pregnancy</keyword><keyword>Respiratory Tract Infections/drug therapy</keyword></keywords><dates><year>2000</year><pub-dates><date>Dec 30</date></pub-dates></dates><isbn>0277-6715 (Print)&#xD;0277-6715</isbn><accession-num>11122505</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]. This is the standard model, known as model 3 in Stewart et al. 2012PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA [9, 10]. This model allows for independent effects of the covariate on risk across trials, known as model 4 in Stewart et al. 2012PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA [8].Model C = One stage random-effects model allowing for aggregation biasPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWxleTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [8].ABBREVIATIONS: AIC = Akaike information criterion, DNC = Model did not converge, NA (cat) = Model not applicable for categorical covariate, NA (ts) = Model not applicable as subgroup defined by trial Table S8. One stage single treatment covariate interaction models for serious adverse eventsInteraction coefficientStandard errorp valueAICShockModel A-0.2820.3430.4111023Model B-0.2880.3440.4031024Model C-0.2420.3560.4971025SepsisModel A-0.2490.4780.6021020Model B-0.2540.4830.5991022Model C-0.6610.5440.2251020ARDS severityModel A-0.224, -0.1970.422, 0.4890.595, 0.6871001Model BDNCDNCDNCDNCModel CNA (cat)NA (cat)NA (cat)NA (cat)CRPModel A0.1770.4140.669730Model B0.1660.4150.689732Model C0.1580.4180.705734Statin doseModel A0.2950.3430.3901021Model B0.2950.3430.3901021Model CNA (ts)NA (ts)NA (ts)NA (ts)Statin typeModel A0.4120.3550.2471021Model B0.4120.3550.2471021Model CNA (ts)NA (ts)NA (ts)NA (ts)Previous statinModel A-0.0980.5210.850722Model B-0.1300.5200.803718Model C-0.0620.5380.909719Model A = One stage random effects model with treatment-covariate interaction ADDIN EN.CITE <EndNote><Cite><Author>Turner</Author><Year>2000</Year><RecNum>79</RecNum><DisplayText>[7]</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="eaa2wewzbza298e5rwxx5zfn2x2szz0a52aa" timestamp="1474149272">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Turner, R. M.</author><author>Omar, R. Z.</author><author>Yang, M.</author><author>Goldstein, H.</author><author>Thompson, S. G.</author></authors></contributors><auth-address>MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. rebecca.turner@ctu.mrc.ac.uk</auth-address><titles><title>A multilevel model framework for meta-analysis of clinical trials with binary outcomes</title><secondary-title>Stat Med</secondary-title><alt-title>Statistics in medicine</alt-title></titles><periodical><full-title>Statistics in Medicine</full-title><abbr-1>Stat. Med.</abbr-1><abbr-2>Stat Med</abbr-2></periodical><alt-periodical><full-title>Statistics in Medicine</full-title><abbr-1>Stat. Med.</abbr-1><abbr-2>Stat Med</abbr-2></alt-periodical><pages>3417-32</pages><volume>19</volume><number>24</number><edition>2000/12/21</edition><keywords><keyword>Clinical Trials as Topic/statistics &amp; numerical data</keyword><keyword>Confidence Intervals</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Likelihood Functions</keyword><keyword>Logistic Models</keyword><keyword>*Meta-Analysis as Topic</keyword><keyword>*Models, Statistical</keyword><keyword>Odds Ratio</keyword><keyword>Outcome Assessment (Health Care)</keyword><keyword>Pre-Eclampsia/drug therapy</keyword><keyword>Pregnancy</keyword><keyword>Respiratory Tract Infections/drug therapy</keyword></keywords><dates><year>2000</year><pub-dates><date>Dec 30</date></pub-dates></dates><isbn>0277-6715 (Print)&#xD;0277-6715</isbn><accession-num>11122505</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[7]. This is the standard model, known as model 3 in Stewart et al. 2012PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA [8].Model B = One stage random effects model with treatment-covariate interactionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW1tb25kczwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+

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ADDIN EN.CITE.DATA [9, 10]. This model allows for independent effects of the covariate on risk across trials, known as model 4 in Stewart et al. 2012PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGV3YXJ0PC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA [8].ABBREVIATIONS: AIC = Akaike information criterion, DNC = Model did not converge, NA (cat) = Model not applicable for categorical covariate, NA (ts) = Model not applicable as subgroup defined by trial Table S9. GRADE Summary of findings table – secondary outcomesSecondary outcomes№ of participants(studies)Quality of the evidence(GRADE)Relative effect(95% CI)Anticipated absolute effectsRisk with PlaceboRisk difference with statin therapyVentilator duration 316(2 RCTs) ????LOW b, c - The mean ventilator duration was 21.45 days MD 1.04 days lower(6.02 lower to 3.93 higher) Requirement for renal replacement therapy 1426(3 RCTs) ????MODERATE bRR 0.97(0.80 to 1.19) 213 per 1,000 6 fewer per 1,000(42 fewer to 40 more) ICU free days to day 28 1743(5 RCTs) ????MODERATE b- The mean ICU free days to day 28 was 11.83 days MD 0.09 days higher(0.75 lower to 0.94 higher) Mortality to day 90 1426(3 RCTs) ????MODERATE b RR 0.97(0.82 to 1.15) 282 per 1,000 8 fewer per 1,000(51 fewer to 42 more) ICU length of stay 1743(5 RCTs) ????MODERATE b - The mean ICU length of stay was 17.93 days MD 0.58 days lower(1.81 lower to 0.64 higher) Hospital length of stay 1487(4 RCTs) ????MODERATE b- The mean hospital length of stay was 32.08 days MD 0.63 days lower(2.59 lower to 1.32 higher) Non-serious adverse events (CK at 10x ULN or ALT/AST at 8x ULN)1755(5 RCTs) ????MODERATE b, dRR 1.40(1.07 to 1.83) 89 per 1,000 36 more per 1,000(6 more to 74 more) *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; ICU: Intensive care unit; MD: Mean difference; RR: Risk ratio; ULN: Upper limit of normalGRADE Working Group grades of evidence – as per table S9. rated moderate due to potential for imprecision given that required information size not met in trial sequential analysisrated moderate due to potential for imprecision given that confidence intervals may include a clinically significant effect in both directionsrated low due to potential for imprecision in effect estimate given reduced sample size and number of trials in this comparisonrated moderate due to potential for imprecision given that these are surrogate outcomesFigure S2. Trial sequential analysis of 28 day mortality.Figure S3. Trial sequential analysis of ventilator free days.Figure S4. Trial sequential analysis of serious adverse events.REFERENCES ADDIN EN.REFLIST 1.Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O'Kane CM, Elborn JS, McAuley DF (2011) A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med 183: 620-626.2.Kruger PS, Harward ML, Jones MA, Joyce CJ, Kostner KM, Roberts MS, Venkatesh B (2011) Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. Am J Respir Crit Care Med 183: 774-781.3.Kruger P, Bailey M, Bellomo R, Cooper DJ, Harward M, Higgins A, Howe B, Jones D, Joyce C, Kostner K, McNeil J, Nichol A, Roberts MS, Syres G, Venkatesh B (2013) A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med 187: 743-750.4.Papazian L, Roch A, Charles PE, Penot-Ragon C, Perrin G, Roulier P, Goutorbe P, Lefrant JY, Wiramus S, Jung B, Perbet S, Hernu R, Nau A, Baldesi O, Allardet-Servent J, Baumstarck K, Jouve E, Moussa M, Hraiech S, Guervilly C, Forel JM (2013) Effect of statin therapy on mortality in patients with ventilator- associated pneumonia: A randomized clinical trial. JAMA 310: 1692-1700.5.McAuley DF, Laffey JG, O'Kane CM, Perkins GD, Mullan B, Trinder TJ, Johnston P, Hopkins PA, Johnston AJ, McDowell C, McNally C (2014) Simvastatin in the Acute Respiratory Distress Syndrome. N Engl J Med 371: 1695-703.6.Truwit JD, Bernard GR, Steingrub J, Matthay MA, Liu KD, Albertson TE, Brower RG, Shanholtz C, Rock P, Douglas IS, deBoisblanc BP, Hough CL, Hite RD, Thompson BT (2014) Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med 370: 2191-2200.7.Turner RM, Omar RZ, Yang M, Goldstein H, Thompson SG (2000) A multilevel model framework for meta-analysis of clinical trials with binary outcomes. Stat Med 19: 3417-3432.8.Stewart GB, Altman DG, Askie LM, Duley L, Simmonds MC, Stewart LA (2012) Statistical analysis of individual participant data meta-analyses: a comparison of methods and recommendations for practice. PLoS One 7: e46042.9.Simmonds MC (2005) Statistical Methodology of individual participant datameta-analysis. PhD Thesis, University of Cambridge. 10.Simmonds MC, Higgins JP, Stewart LA, Tierney JF, Clarke MJ, Thompson SG (2005) Meta-analysis of individual patient data from randomized trials: a review of methods used in practice. Clin Trials 2: 209-217.11.Riley RD, Lambert PC, Abo-Zaid G (2010) Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ 340: c221.12.Riley RD, Steyerberg EW (2010) Meta-analysis of a binary outcome using individual participant data and aggregate data. Research synthesis methods 1: 2-19. ................
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