Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults—Authors’ reply
Authors: B. Pertzov, N. Eliakim-Raz, H. Atamna, A.Z. Trestioreanu, D. Yahav, L. Leibovici
Journal: Clinical Microbiology and Infection (2019)

We would like to thank Dr Zhou and his colleagues for their interest in our paper and for taking the time to express their concerns [1Zhou X. Tang G. Statin therapy has no effect on the mortality of adult patients with sepsis? Perhaps not.Clin Microbiol Infect. 2019; ([cited 2019 Aug 21];0(0). Available from:)https://www.clinicalmicrobiologyandinfection.com/article/S1198-743X(19)30220-4/abstractAbstract Full Text Full Text PDF Scopus (2) Google Scholar, 2Pertzov B. Eliakim-Raz N. Atamna H. Trestioreanu A.Z. Yahav D. Leibovici L. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults—a systematic review and meta-analysis.Clin Microbiol Infect. 2019; 25: 280-289Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar]. In his letter to the editor, Dr Zhou notes potential concerns regarding the inclusion criteria and sample size of this analysis, and this is our reply. Dr Zhou and colleagues stated that the studies by McAuley et al. and Makris et al. [3McAuley D.F. Laffey J.G. O'Kane C.M. Perkins G.D. Mullan B. Trinder T.J. et al.Simvastatin in the acute respiratory distress syndrome.N Engl J Med. 2014; 371: 1695-1703Crossref PubMed Scopus (309) Google Scholar, 4Makris D. Manoulakas E. Komnos A. Papakrivou E. Tzovaras N. Hovas A. et al.Effect of pravastatin on the frequency of ventilator-associated pneumonia and on intensive care unit mortality: open-label, randomized study.Crit Care Med. 2011; 39: 2440-2446Crossref PubMed Scopus (65) Google Scholar] included patients without sepsis. Although this is true, the authors kindly agreed to send us individual patient data for the analysis and we acknowledged their assistance in our publication. Therefore, we were able to include only patients with sepsis. This also explains why different numbers are reported in the trial's manuscript and our meta-analysis. Dr Zhou and colleagues also stated that patients included in the studies by the groups of Papazian, Novack and Viasus do not fulfil the definition of sepsis [5Papazian L. Roch A. Charles P.E. Penot-Ragon C. Perrin G. Roulier P. et al.Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial.JAMA. 2013; 310: 1692-1700Crossref PubMed Scopus (150) Google Scholar, 6Novack V. Eisinger M. Frenkel A. Terblanche M. Adhikari N.K. Douvdevani A. et al.The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial.Intens Care Med. 2009; 35: 1255-1260Crossref PubMed Scopus (120) Google Scholar, 7Viasus D. Garcia-Vidal C. Simonetti A.F. Dorca J. Llopis F. Mestre M. et al.The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.BMJ Open. 2015; 5e006251Crossref PubMed Scopus (34) Google Scholar]. Papazian et al. included patients with a Modified Clinical Pulmonary Infection Score (CPIS) [[8]Fartoukh M. Maitre B. Honoré S. Cerf C. Zahar J.R. Brun-Buisson C. Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited.Am J Respir Crit Care Med. 2003; 168: 173-179Crossref PubMed Scopus (258) Google Scholar] of at least 5 and an infectious source by culture [[5]Papazian L. Roch A. Charles P.E. Penot-Ragon C. Perrin G. Roulier P. et al.Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial.JAMA. 2013; 310: 1692-1700Crossref PubMed Scopus (150) Google Scholar]. The CPIS includes temperature, white blood count, FIo2, tracheal secretions and chest X-ray evaluation. Therefore, mechanically ventilated patients with high CPIS and an infectious source clearly fulfil the criteria for sepsis. Hence, we think these patients were rightfully included. Novack et al. included patients with documented or suspected bacterial infection that required hospital admission and intravenous therapy [[6]Novack V. Eisinger M. Frenkel A. Terblanche M. Adhikari N.K. Douvdevani A. et al.The effects of statin therapy on inflammatory cytokines in patients with bacterial infections: a randomized double-blind placebo controlled clinical trial.Intens Care Med. 2009; 35: 1255-1260Crossref PubMed Scopus (120) Google Scholar]. Viasus et al. included patients with pneumonia who required hospital admission [[7]Viasus D. Garcia-Vidal C. Simonetti A.F. Dorca J. Llopis F. Mestre M. et al.The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.BMJ Open. 2015; 5e006251Crossref PubMed Scopus (34) Google Scholar]. These patients had mild sepsis and differed from patients with sepsis in the intensive care unit. Nevertheless, we thought they represent a population of patients similar to our population of interest as defined in the inclusion criteria; and that their exclusion bears a larger risk of bias than their inclusion. In a sensitivity analysis withdrawing these studies, the main results do not change. The authors have performed a trial sequential analysis and calculated that the optimal sample size for this analysis is 12 151 patients. In our study we have calculated the sample size needed to show a superiority for statin treatment, for the effect size that we have found (RR 0.96) and reached a far larger number of 77 800. We are in agreement with Dr Zhou and colleagues that currently the randomized controlled trials conducted, to evaluate the benefit of statins for sepsis, have not reached the required collective sample size. However, as none of the randomized controlled trials published found a significant reduction in mortality for statin treatment and powered studies will require tremendous resources, it is our opinion that further studies are not warranted. •The discrepancies in population size between the manuscript of McAuley et al. and this meta-analysis are not errors. They are due to individual patient data that were kindly given to us by the author.•We thank the authors of this letter for pointing our attention to the following errors in Table 1 of this manuscriptoThe mean age of the placebo and statin group in the study by Prado et al. [[9]Prado K. Ribeiro C. Furian T. Pinto Ribeiro R. Silvello D. Rohde L. et al.A clinical randomized trial on the use of atorvastatin in patients with sepsis or septic shock: effects on endothelial function.Crit Care. 2013; 17: P6Google Scholar] were switched.oThe dose of statin given in the study by Truwit et al. [[10]Truwit J.D. Bernard G.R. Steingrub J. Matthay M.A. Liu K.D. Albertson T.E. Rosuvastatin for sepsis-associated acute respiratory distress syndrome.N Engl J Med. 2014; 370: 2191-2200Crossref PubMed Scopus (366) Google Scholar] was a 40 mg loading dose and a daily dose of 20 mg and not a daily dose of 40 mg as written.oThe female population at Shao et al. [[11]Shao H. Wang C. Zhu W. Huang X. Guo Z. Zhang H. et al.Influence of simvastatin treatment on Toll-like receptor 4 in monocytes of peripheral blood in patients with sepsis and severe sepsis.Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2016; 28: 159-163PubMed Google Scholar] was 90 patients and not 92 patients as written. In conclusion we would like to thank Dr Zhou and colleagues for their comprehensive and valuable review of our study. We stand behind the methodology of our analysis and results and think that the correct population and studies were included. The authors have no conflict of interest to declare. No commercial or external finding was received for this review.