Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials
- 1.4k Downloads
We performed an individual patient data meta-analysis to assess the possible benefits and harms of statin therapy in adults with acute respiratory distress syndrome (ARDS) and to investigate effects in specific ARDS subgroups.
We identified randomised clinical trials up to 31 October 2016 that had investigated statin therapy versus placebo in patients with ARDS. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed for primary and secondary outcomes, and one-stage regression models with single treatment–covariate interactions for subgroup analyses. Risk of bias was assessed using the Cochrane Risk of Bias Tool.
Six trials with a total of 1755 patients were included. For the primary outcomes, there was no significant effect of statin therapy on 28-day mortality [relative risk (RR) 1.03, 95% CI 0.86–1.23], ventilator-free days (mean difference 0.34 days, 95% CI −0.68 to 1.36) or serious adverse events (RR 1.14, 95% CI 0.84–1.53). There was a significantly increased incidence of raised serum creatine kinase or transaminase levels with statin therapy (106/879; 12.1%) versus control (78/876; 8.9%) (RR 1.40, 95% CI 1.07–1.83, p = 0.015). There were no significant treatment–covariate interactions in the predefined subgroups investigated.
We found no clinical benefit from initiation of statin therapy in adult patients with ARDS, either overall or in predefined subgroups. While there was an increased incidence of raised serum creatine kinase and transaminase levels, there was no difference in serious adverse events among groups. Therefore, we do not recommend initiation of statin therapy for the treatment of ARDS.
KeywordsStatin ARDS ALI Meta-analysis
We are grateful to the investigators and clinical trials groups of all the trials included in this study for providing access to their trial data. ACG is grateful for support from the National Institute for Health Research Comprehensive Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. ACG and DFM are grateful for support from the UK Intensive Care Foundation.
Compliance with ethical standards
There was no specific funding for this study. The HARP2 trial was supported by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership (08/99/08). The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office (CSO) in Scotland and National Institute for Social Care and Health Research (NISCHR) in Wales and the Health & Social Care (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.
Conflicts of interest
DMcA reports Grants from the National Institute for Health Research, Efficacy and Mechanism Evaluation, the Health Research Board, Health and Social Care Research & Development office, the Intensive Care Society Ireland, and REVIVE to support the conduct of HARP-2. Outside the submitted work, DMcA reports personal fees from consultancy for GlaxoSmithKline (GSK), SOBI, Bayer, Boehringer Ingelheim and Peptinnovate. His institution has received grants from the NIHR and others, as well as funds from GSK for DMcA undertaking bronchoscopy as part of a clinical trial. In addition, DMcA also holds a patent for the use of a pharmacotherapy (not a statin) for treatment of ARDS awarded to Queen’s University Belfast. BTT reports Grants from the National Heart, Lung, and Blood Institute of the National Institute of Health. Outside the submitted work, BTT reports personal fees from consultancy for Alexion, Asahi Kasei, Boehringer Ingelheim, GlaxoSmithKline, and Regeneron. ACG reports, outside the submitted work, grants from the National Institute for Health Research that he has received speaker fees from Orion Corporation Orion Pharma and Amomed. He has consulted for Ferring Pharmaceuticals, Tenax Therapeutics and received Grant support from Orion Corporation Orion Pharma, Tenax Therapeutics and HCA International with funds paid to his institution. Other authors declare that they have no conflicts of interest.
- 1.Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R (1994) The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818–824Google Scholar
- 3.Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A (2016) Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315:788–800CrossRefPubMedGoogle Scholar
- 7.Cheung AM, Tansey CM, Tomlinson G, Diaz-Granados N, Matte A, Barr A, Mehta S, Mazer CD, Guest CB, Stewart TE, Al-Saidi F, Cooper AB, Cook D, Slutsky AS, Herridge MS (2006) Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome. Am J Resp Crit Care Med 174:538–544CrossRefPubMedGoogle Scholar
- 9.Shyamsundar M, McAuley DF, Shields MO, MacSweeney R, Duffy MJ, Johnston JR, McGuigan J, Backman JT, Calfee CS, Matthay MM, Griffiths MJ, McDowell C, Elborn SJ, O’Kane CM (2014) Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial. Ann Surg 259:26–31CrossRefPubMedGoogle Scholar
- 16.Alhazzani W, Truwit J (2016) Statins in patients with sepsis and ARDS: is it over? Yes. Intensive Care Med. doi: 10.1007/s00134-016-4585-z
- 17.Kruger PS, Terblanche M (2016) Statins in patients with sepsis and ARDS: is it over? No. Intensive Care Med. doi: 10.1007/s00134-016-4564-4
- 18.McAuley D, Charles PE, Papazian L (2016) Statins in patients with sepsis and ARDS: is it over? We are not sure. Intensive Care Med. doi: 10.1007/s00134-016-4454-9
- 19.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 Resp Crit Care Med 187:743–750CrossRefPubMedGoogle Scholar
- 22.Horsley T, Dingwall O, Sampson M (2011) Checking reference lists to find additional studies for systematic reviews. Cochrane Database Syst Rev: MR000026Google Scholar
- 24.Higgins JPT, Green S (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane CollaborationGoogle Scholar
- 26.Choi HS, Park MJ, Kang HM, Kim YJ, Choi CW, You JH (2008) Statin use in sepsis due to pneumonia [Abstract]. American Thoracic Society International Conference, May 16–21, 2008, TorontoGoogle Scholar
- 31.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 310:1692–1700CrossRefPubMedGoogle Scholar
- 32.Deshpande A, Pasupuleti V, Rothberg MB (2015) Statin therapy and mortality from sepsis: a meta-analysis of randomized trials. Am J Med 128(410–417):E411Google Scholar
- 34.Mansur A, Steinau M, Popov AF, Ghadimi M, Beissbarth T, Bauer M, Hinz J (2015) Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study. BMC Med 13:128CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Ouellette DR, Moscoso EE, Corrales JP, Peters M (2015) Sepsis outcomes in patients receiving statins prior to hospitalization for sepsis: comparison of in-hospital mortality rates between patients who received atorvastatin and those who received simvastatin. Ann Intensive Care 5:9CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Zhang Z, Ni H, Xu X (2014) Do the observational studies using propensity score analysis agree with randomized controlled trials in the area of sepsis? J Crit Care 29:886.e889–815Google Scholar
- 43.Shyamsundar M, McKeown ST, O’Kane CM, Craig TR, Brown V, Thickett DR, Matthay MA, Taggart CC, Backman JT, Elborn JS, McAuley DF (2009) Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. Am J Resp Crit Care Med 179:1107–1114CrossRefPubMedPubMedCentralGoogle Scholar
- 44.Blackwood B, Ringrow S, Clarke M, Marshall J, Rose L, Williamson P, McAuley D (2015) Core Outcomes in Ventilation Trials (COVenT): protocol for a core outcome set using a Delphi survey with a nested randomised trial and observational cohort study. Trials 16:368CrossRefPubMedPubMedCentralGoogle Scholar