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Abstract. – OBJECTIVE: Approximately 7.5% of patients admitted to Intensive Care Unit (ICU) of hospitals are likely diagnosed with acute lung injury (ALI) or acute respiratory distress syn-drome (ALI/ARDS), and more than one-third of the affected patients die with this disease. De-spite the improvement in patient care with the availability of mechanical ventilators, mortality among these patients is unabated. Even though many drugs proved effective in preclinical stud-ies, none is efficacious clinically, and no phar-macological treatment is insight. Statins were reported to exert anti-inflammatory effects and it was suggested that these drugs may be use-ful in ALI/ARDS patients. However, the initial positive results with statins were not confirmed in later studies, raising doubts about their use-fulness. In the present meta-analysis, we exam-ined the efficacy of statins in ALI/ARDS patients.

MATERIALS AND METHODS: Various data-bases were searched to identify both randomized clinical trials and cohort studies, where statin users were compared to non-statin users. To increase the strength of the analysis, cohort studies and random clinical trials were combined in the present analysis. RevMan software from the Cochrane Col-laboration was used to a conduct meta-analysis.

RESULTS: Baseline characteristics indicated that APACHE-III score to be lower in statin us-ers, suggesting some beneficial effects. However, mortality and severe sepsis were unchanged fol-lowing statin treatment. But results also showed reduced SOFA score and increased number of ven-tilator-free days among statin users, indicating that statins are likely to have some beneficial effects.

CONCLUSIONS: Statin treatment of ALI/ARDS patients seems to improve health in terms of organ failure and also by lowering the need for ventilation. However, the sample size is too small to accurately assess the effects on mortality and sepsis and further investigations are needed.

Key WordsAcute lung injury, Acute respiratory distress syn-

drome, Statins, APACHE-III, SOFA score, Severe sep-sis, Inflammation.

Introduction

An injury to lungs, caused by either direct or indirect insult, leads to a serious illness called acute lung injury (ALI) or acute respiratory dis-tress syndrome, which often have fatal conse-quences. Approximately 7.5% of patients admit-ted to intensive care unit of hospitals in many countries are likely diagnosed with ALI/ARDS1,2, making this disease, a common medical emergen-cy. More than one-third of the affected patients die with this disease3. Clinical description of ARDS was first made in 19674 and after sever-al modifications, the ‘Berlin definition’ is wide-ly accepted, which states that “ARDS is an acute diffuse, inflammatory lung injury”, with different clinical presentations with regard to the extent of oxygenation, duration of injury and radiological parameters5. The predominant common compli-cations of ARDS are pneumonia and severe sepsis and these are generally accompanied by acute al-veolar neutrophilic infiltrate and diffuse alveolar damage, depending upon the severity of ARDS6,7. Fundamental features of ARDS are inflammation and injury at the junction of alveolar epithelium and capillary endothelium, accompanied by the activation of neutrophils and macrophages, and release of inflammatory cytokines8. Unfortunate-ly, no effective therapeutic intervention is avail-able to prevent ARDS and to reduce mortality and morbidity in patients suffering from ALI/ARDS, even though significant efforts have been made. Many of the clinical procedures that have been shown to lower mortality in ARDS patients are specific towards people affected by ventilator-in-duced lung injury9,10.

Several pharmacological approaches including b2-adrenergic agonists, exogenous surfactants, immunomodulating agents, and statins have been tried in ARDS patients without any conclusive outcomes11,12. This lack of efficacy is generally

European Review for Medical and Pharmacological Sciences 2018; 22: 3190-3198

Y. FENG

Department of Respiratory Medicine, Ruikang Hospital Affiliated To Guangxi Traditional Chinese Medicine University, Nanning, Guangxi, China

Corresponding Author: Yuan Feng, MM; e-mail: feng_yuan1212@163.com

Efficacy of statin therapy in patients with acuterespiratory distress syndrome/acute lung injury:a systematic review and meta-analysis

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ascribed to the complexity and heterogeneity of ARDS pathogenesis and also the appropriate tim-ing of therapeutic intervention13. The therapeutic use of statins for the management of ALI/ARDS was suggested based on the results of animal stud-ies. These reports showed that statins could lower inflammation and vascular leak, and thus prevent organ dysfunction. These animal studies were fol-lowed by a prospective cohort study from Ireland, demonstrating a trend for reduced mortality in ICU patients with ARDS receiving statins14. However, a subsequent retrospective cohort study failed to observe any beneficiary effect of statins in ARDS patients15. Because of these discrepancies, we have conducted the present meta-analysis of results from all available cohort studies and clinical trials to assess whether statin therapy has any beneficia-ry effect in ALI/ARDS patients.

We have conducted a meta-analysis of clinical trials and cohort studies that examined the effi-cacy of statin therapy in ARDS/ALI patients, in reducing mortality and morbidity and also sep-sis-related organ failure assessment (SOFA), in comparison with non-statin users.

Materials and Methods

Study Selection Criteria for Meta-analysis In this meta-analysis review, we included ran-

domized controlled clinical trials and cohort stud-ies that tested the efficacy of statins, with place-bo-treated controls, in intensive care unit (ICU) admitted patients with ALI/ARDS. The included studies assessed mortality and ventilator-free days. There are 8 cohort studies and 4 randomized clin-ical trials in this meta-analysis. Since the idea that statins can be beneficial to ARDS patients sur-faced from animal studies conducted in 2008, all the clinical studies included in the present analy-sis were conducted during and after the year 2008. These studies assessed either Apache-III score or SOFA score, sepsis, the number of ventilation free days during 7 to 28-day ICU hospitalization in ALI/ARDS patients receiving statins or no statin therapy. The studies were selected with the con-sideration for similar statin doses, but were not re-stricted to the type of statin used.

Search MethodsRelevant published information and scientific

papers were searched in several databases includ-ing Scopus, PubMed, Google Scholar, and Web of Science. MeSH terms for the search were acute

lung injury, acute respiratory distress syndrome, ARDS, ALI, sepsis, lung injury, randomized con-trolled trial, atorvastatin, simvastatin, rosuvasta-tin, fluvastatin, pravastatin, lovastatin, pitavas-tatin and cohort studies. Only English language publications and information were collected and screened for relevance to the meta-analysis, ini-tially at the title and abstract level. Once they were found to be relevant, full reports and supplemen-tal information files were retrieved and the data were extracted and normalized to uniformity.

Data Collection and Analysis and Quality Assessment

The following data were collected from the studies included in the meta-analysis: details of institutions where the studies were conducted, details of the authors and publication details, the total number of patients studied and the actu-al number of patients included in the final anal-yses, in statin-treated and placebo or non-statin groups, age, and sex of the studied patients. The type of statin used and its dosage were recorded but were not used in inclusion/exclusion criteria. Baseline parameters collected from these stud-ies include APACHE (Acute Physiology, Age, Chronic Health Evaluation) III score, the number of patients affected with pneumonia, sepsis with-out shock, severe sepsis with shock, have direct lung injury and SOFA (Sepsis-related Organ Fail-ure Assessment) score. Statin treatment efficacy parameters measured in these studies included mortality during ICU stay, improvement in SOFA score, the number of ventilator-free days, the number of patients with severe sepsis reported.

All the authors of this meta-analysis/systematic review independently screened the abstracts of col-lected studies initially and participated in the selec-tion of relevant clinical studies. In the subsequent step, all the authors screened through the full texts of all selected studies and independently collected the data for meta-analysis. The pooled information was then reviewed collectively and regular discussions were held during this work to resolve any discrep-ancies or differences of opinion to reach consensus.

Statistical AnalysisWe used methods suggested by the Cochrane

Collaboration guidelines for meta-analysis. The statistical analyses were performed by Review Manager (RevMan) version 5.3 (The Cochrane Collaboration, London, United Kingdom). The effect of statin treatment was analyzed by ap-plying Mantel-Haenszel statistics were applied

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in the random-effect model, for all the analyses and Odds ratios (OR) were derived at 95% con-fidence intervals (CI). Mean difference analyses in inverse variance (IV) fixed mode at 95% con-fidence intervals were conducted for assessing statin treatment effect on ventilator-free days and SOFA score. Sensitivity analysis was performed one study was excluded when we were analyzing the results. We also performed this analysis only for the cohort studies or for the RCT studies.

Results

A total of 9281 studies were identified from the databases, using the search MeSH terms listed in the Methods section and these reports consist-ed of both clinical and non-clinical/experimental studies. Initial screening was done at the title and abstract level for relevancy resulted in the exclu-sion of 5714 studies (Figure 1). Relevancy criteria for selection of studies are if it is clinical, involves patients, a patient cohort study, dealing with pa-tients who have ARDS/ALI and are treated with statins. The second round of screening on the ba-sis of these relevancy criteria led to the exclusion of another 2442 studies. Further examination of

data reported in the remaining studies and the de-sign of the studies and also if the right kind of controls is included, resulted in the removal of an-other 1101 studies. Finally, there were 24 studies that are relevant, from which 12 studies were se-lected on the basis of availability of relevant data for both controls and statin users and similarity of the study design. These 12 studies included 8 cohort studies and 4 random controlled clinical trials (Table I), with a total of 9309 patients. In-clusion criteria were: (1) patients suffered ARDS or ALI; (2) patients received a statin drug during their stay in ICU without or with prior statin ex-posure; (3) study included matched control pa-tients who were non-statin users. Among the total 9309 patients, 2652 were statin users, whereas 6657 patients were non-users of statin. Study/pa-tient selection was not discriminated on the basis of the type of statin, which included simvastatin, rosuvastatin, atorvastatin, and pravastatin, and the dosage (ranging from 10 mg to 80 mg) used. The included studies (Table I) were: Bajwa et al, 201216; Bruyere et al, 201417; Craig et al, 201118; Dinglas et al, 201619; Irish Cohort 200814; Kor et al, 200915; Mansur et al, 2015 20; McAuley et al, 201421; Truwit et al, 201412; O’Neal et al, 201122; Terblanche et al, 201123; Yadav et al, 201424.

Figure 1. Flow chart of study se-lection for the meta-analysis.

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Patient characteristicsPatients in the statin-treated group are 63

years old on the average whereas the patients in non-statin user group are 58 years old. There was significant male preponderance among recruited patients in both the groups, with ~60% of the non-statin users and 63.5% of the statin-users being males (Table II). The baseline Apache-III score, which is a tool to predict mortality risk among hospitalized critically ill patients, on the average was significantly higher (p < 0.001) in the non-statin user group (mean ±SD, 89±21; range 81 to 95) as compared to the statin-us-ers (82.6±21.5; range 66.5 to 92). This elevated Apache-III score indicated that the risk of mor-tality among non-statin using ARDS/ALI pa-tients is much higher. The proportion of patients with pneumonia in the statin group is consid-erably higher (Table III) than that in non-statin users (Odds ratio, 1.386; 95% CI, 1.232 to 1.559; p < 0.0001). However, the proportion of patients with sepsis without shock is less in statin us-ing ARDS patients (Odds ratio, 0.788; 95% CI, 0.688 to 0.901; p = 0.0005). On the other hand, a wide number of patients suffered sepsis with shock in statin group as compared to non-statin users (Odds ratio, 2.264; 95% CI, 1.95 to 2.63; p < 0.0001). The incidence of direct lung injury is similar in both the groups (Odds ratio, 1.104; 95% CI, 0.989 to 1.231; p = 0.074) (Table III). The baseline values of SOFA score were similar between the two groups of patients (Table II).

Response to statin treatmentOdds ratio (OR) analysis (Mantel-Haenszel

statistics, Random) revealed no significant dif-ference (OR, 0.92; 95% CI of 0.74 and 1.15; p = 0.49) between statin users and non-users in the occurrence of mortality (Figure 2). All the twelve studies were included in this analysis, which re-vealed no beneficial effect of statin treatment to ARDS patients. The occurrence of severe sepsis was compared between statin users and non-us-ers only in three studies. Again, odds ratio analy-sis indicated no significant difference (OR, 0.99; 95% CI of 0.62 and 1.60; p = 0.98) between these groups (Figure 3). Odds ratio analysis of ARDS occurrence in patients with lung injury (OR, 0.73; 95% CI of 0.45 and 1.21; p = 0.22) also indicated no beneficial effect of statin treatment (Figure 4).

Comparative effect of statin treatment on SOFA score was reported in five studies. Mean difference analysis (Mantel-Haenszel statistics, IV, Fixed mode) of SOFA score revealed (Figure 5) significant differences between statin users and non-users, with non-users showing higher score (p < 0.00001). This suggested that statin treatment has some beneficial effect in reducing the risk of sepsis-related failure of organs in ARDS/ALI pa-tients. Similar beneficial effects are also noticed on the “ventilation free days” among ARDS/ALI patients. Thus, mean difference analysis showed a significantly increased number of ventilation-free days in statin-treated patients (p < 0.00001) as compared to untreated patients (Figure 6).

Table I. Details of the included studies.

Obs, Observational; db, double blind; RCT, randomized controlled clinical trial

Study Year Type of study Statin users Statin non-users

No. of %Males Age No. of %Males Age patients patients

Bajwa et al 2012 Cohort/Obs 413 62 68.4 2330 62 58.1Bruyere et al 2014 Cohort 93 83 68 256 68 63Craig et al 2011 RCT, db 30 73 52.5 30 73 52.8Dinglas et al 2016 RCT, blinded 379 49 54 366 49 54Irish Cohort 2008 Cohort 24 57 67.8 172 62 56.7Kor et al 2009 Cohort 45 58 70 133 50 63Mansur et al 2015 Cohort/Obs 108 76 70 296 65 60McAuley et al 2014 RCT, db 259 53 53.2 280 61 54.4Truwit et al 2014 RCT, db 379 49 54.2 366 49 54.1O'Neal et al 2011 Cohort 149 56.4 65 426 56.1 57Terblanche et al 2011 Cohort 219 75 67.4 1178 62.1 55.5Yadav et al 2014 Cohort 722 71.3 70.2 1123 62.6 66.5

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Study Statin users Statin non-users APACHE No Sepsis/ Sepsis/ Direct SOFA APACHE No. Sepsis/ Sepsis/ Direct SOFA III with no shock Shock Lung III with no shock Shock lung Score Pneumonia injury Score pneumonia injury

Bajwa et al, 2012 66.5 ± 19.1 222 117 220 233 — 81.0 ± 17.9 1177 774 1126 1315 —

Bruyere et al, 2014 — 33 — 33 33 9.5 ± 3 — 100 — 74 66 9.3 ± 3.3

Craig — — — — 17 10.2 ± 3 — — — — 17 10.4 ± 3.9 et al, 2011

Dinglas 92 ± 28 267 — 173 — — 95 ± 28 260 — 166 — — et al, 2016 SAILS

Irish Cohort, — 7 4 — — — — — — — — — 2008

Kor 80 ± 9 — 16 — 31 7 ± 1 84 ± 11 — 82 — 76 9 ± 1.2 et al, 2009

Mansur — 75 52 56 75 8.9 ±3.4 — 169 95 201 169 9.9 ± 3.8 et al, 2015

McAuley — 161 189 — — 8.5 ± 3.2 — 154 218 — — 8.8 ± 2.9 et al, 2014

Truwit 92 ± 28.4 267 — 173 267 — 94.8 ± 28 260 — 166 260 — et al, 2014

O'Neal — — 63.3 — — — — — 234 — — — et al, 2011

Terblanche — — 5 — — 4 ±0.5 — — 39 — — 3 ± 0.6 et al, 2011

Yadav — — — — 278 — — — — — 351 — et al, 2014

Table II. Baseline characteristics of patients included in the meta-analysis.

SOFA, Sepsis-related Organ Failure Assessment score; APACHE, Acute Physiology, Age, Chronic Health Evaluation

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Table III. Odds ratio analysis of baseline characteristics of patients included in the meta-analysis.

Condition Odds 95% p Ratio CI

Pneumonia 1.386 1.232 to 1.559 <0.0001Sepsis, no shock 0.788 0.688 to 0.901 0.0005Sepsis, with shock 2.264 1.95 to 2.63 <0.0001Direct lung injury 1.104 0.989 to 1.231 0.074

Figure 2. Effect of statins on the occurrence of mortality among ARDS/ALI patients. Odds ratio analysis (Mantel-Haenszel sta-tistics, Random mode) was conducted on the occurrence of mortality in statin users and non-users, at 95% confidence intervals.

Figure 3. Effect of statins on the occurrence of severe sepsis among ARDS/ALI patients. Odds ratio analysis (Mantel-Haenszel sta-tistics, Random mode) was conducted on the occurrence of severe sepsis in statin users and non-users, at 95% confidence intervals.

Figure 4. Effect of statins on ARDS occurrence among lung injury patients. Odds ratio analysis (Mantel-Haenszel statistics, Random mode) was conducted on the occurrence of ARDS in statin users and non-users, at 95% confidence intervals.

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Discussion

ARDS is a common emergency situation with characteristic impaired gas exchange, edema of lungs and inflammation25. Patients suffering from ARDS are mechanically ventilated in Intensive Care Units (ICU). Even though the ventilator strat-egies are used for the protection of lungs, ARDS patients suffer from high mortality; with up to 40% of the admitted patients, there are no effective phar-macological options available26. Despite promising results in preclinical studies27,28, many of the phar-macological interventions failed in clinical trials in preventing death and in improving other outcomes in ARDS patients. Considering that statins exert an-ti-inflammatory effects through novel mechanisms and were found to be effective in neurological dis-eases as well as organ transplantations, it is specu-lated that this class of drugs may be useful in ARDS patients also. Some studies29-32 indicated such effi-cacy by statins in sepsis and ARDS. In some of the initial studies14,15,18 evaluating the efficacy of statins in ALI/ARDS patients, the results were modest to underwhelming. Even though there were some in-dications of beneficial effects of statin therapy in re-

ducing the incidence of ARDS, further analysis of these results indicated no significant association16. A recent meta-analysis33 on the impact of statin ther-apy on ALI/ARDS, which included 3 RCTs and 6 cohort studies, concluded that statin therapy had no effect on mortality or ventilator-free days in the hos-pitalized ALI/ARDS patients. Another meta-anal-ysis34 also suggested that statins are without any beneficial effect in ALI/ARDS patients either for reducing mortality or for improving ventilator-free days. However, there were several limitations due to sampling bias in these studies.

In the present meta-analysis, we tried to ad-dress the question of whether or not statins have any beneficial effect in ALI/ARDS patients. In ac-cordance with the earlier studies, we also observed that statins do not curtail the occurrence of mortal-ity in these patients. However, in order to counter the limitation due to fewer numbers of studies, we combined the RCTs and the cohort studies to in-crease the number of included studies. Some of the patients in the statin user group were taking statins before the initiation of the research. Probably be-cause of this, the baseline APACHE-III score was significantly lower in statin users. However, this

Figure 5. Effect of statins on SOFA score among ARDS/ALI patients. Forest plot of mean difference analyzed by Inverse variance (IV) analysis in fixed-effect model at 95% confidence intervals (CI).

Figure 6. Effect of statins on Ventilation free days among ARDS/ALI patients. Forest plot of mean difference analyzed by Inverse variance (IV) analysis in fixed-effect model at 95% confidence intervals (CI).

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did not reflect in the SOFA score, which predicts the organ failure. But despite the lower baseline APACHE-III score in statin users, the mortality in these patients was not different from statin non-us-ers. This disconnect can be due to large heteroge-neity in the included patients or it is simply because of the lack of protective effect of statins.

Even though there was no beneficiary effect on mortality and sepsis, statin usage led to significant-ly lowered SOFA score as well as improved venti-lator-free days in ALI/ARDS patients. These results were different from earlier meta-analyses33,34, which is possibly due to the combined analysis of RCTs and cohort studies in this meta-analysis, which was done to increase the strength of sample size to the present analysis. The fact that statin users benefited in terms of lower SOFA score and increased ventilator-free days indicated that the anti-inflammatory action of this class of drugs is indeed helpful to ARDS patients. Therefore, the present meta-analysis indicates that while statins may not alleviate the overall mortality in ARDS patients, these drugs help in lowering or-gan failure and facilitate the recovery of pulmonary function. Unfortunately, APACHE-III score was not reported in all the included studies, following statin treatment. But considering the baseline APACHE-III scores, it can be suggested that a larger number of studies with more patients and appropriate place-bo-treated control group are needed to assess whether statins also lower the risk of higher mortality.

Conclusions

There is still a glimmering hope for the use of statins in ALI/ARDS patients. Indeed, as sug-gested earlier22, a combination of statin therapy with another drug such as aspirin can be more effective than statins alone and this needs to be addressed thoroughly.

Conflict of InterestAll authors declare no conflict of interest.

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