Effect of statins on neurological functional outcomes in critically ill adult patients with traumatic brain injury: a systematic review and meta-analysis ========================================================================================================================================================= * Charles Veillette * Mauricio Umana * Marc-Aurèle Gagnon * Olivier Costerousse * Ryan Zarychanski * Daniel F McAuley * Patrick Lawler * Francois Lauzier * Shane W English * Lynne Moore * Chartelin Jean Isaac * Alexis F Turgeon ## Abstract **Background** Statins are considered a promising therapy in traumatic brain injury (TBI) because of their role in mediating inflammatory injury and other endothelial properties. Whether they can improve patient outcomes is unknown. **Objectives** To evaluate the effect of statins in critically ill patients with TBI. **Design** Systematic review and meta-analysis of randomised controlled trials. **Eligibility criteria** Trials of adult patients with acute moderate or severe TBI. **Methods** We searched Medline, Embase, Cochrane Central and Web of Science databases for trials comparing the use of any statin with placebo or other interventions. Our primary outcome was the Glasgow Outcome Scale (GOS or GOS extended); secondary outcomes were mortality, intensive care unit (ICU) and hospital length of stay. We used inverse variance random-effects models to calculate risk ratios (RR) and weighted mean differences. We assessed the risk of bias of trials using the Cochrane risk of bias assessment tool and the presence of statistical heterogeneity using the I2 index. Levels of evidence for summary effect measures were evaluated using Grading of Recommendations Assessment, Development and Evaluation methodology.1 **Results** Of the 2418 retrieved records, 7 trials met our eligibility criteria. Three studied simvastatin, and four studied atorvastatin. The duration of the intervention ranged from 2 to 10 days, and outcomes were assessed between ICU discharge and 6 months. Five trials were considered at high risk of bias. We observed no statistically significant association between statins and the GOS (RR 0.42; 95% CI, 0.14 to 1.22; two trials; n=84, I2=0%; very low certainty) or mortality (RR 0.59; 95% CI, 0.25 to 1.44; three trials; n=160, I2=0%; very low certainty). No significant effect was observed for ICU length of stay, while hospital length of stay was evaluated in one trial showing shorter duration. **Conclusion** We found no conclusive evidence supporting the use of statins in critically ill adult patients with TBI at this time. Nevertheless, the trials were limited, and wide confidence intervals resulted in significant uncertainty of the findings. A potential benefit cannot be ruled out, underscoring the need for a larger, well-designed trial. **PROSPERO registration number** CRD42023421227. * Brain Injuries * Drug Therapy * Adult intensive & critical care * Neurological injury * Systematic Review ### STRENGTHS AND LIMITATIONS OF THIS STUDY * Our systematic review was designed to look at recommended patient-centred clinical outcomes to evaluate interventions in critically ill patients with traumatic brain injury. * Only randomised controlled trials were considered. * Only a small number of trials were identified, and the level of evidence of our findings is limited. * Some registered trials are completed but still unpublished. ## Introduction Traumatic brain injury (TBI) affects tens of millions of individuals worldwide each year, and its incidence is increasing over time.1 2 Despite major advances in our understanding of the disease, the optimal management of TBI patients remains uncertain, mainly focusing on preventing secondary cerebral injuries. Among the various treatment options, reducing oxidative stress has been considered one of the priorities.3 Statins are among drug interventions that have been considered promising for their anti-inflammatory properties and other endothelial properties, independently of their low-density lipoprotein-cholesterol lowering effect.4 5 Because they are readily available worldwide and relatively cheap, their use could easily be integrated into practice. Nevertheless, evidence supporting their use in critically ill patients with TBI is unclear, with preclinical studies showing promising results but clinical studies reporting conflicting ones.6–12 Findings from previous systematic reviews are also conflicting,13–20 which could be explained by differences in methods with the inclusion of non-randomised studies, TBI subpopulations or in looking at the effect of the use of statins before the TBI.14 18 20 21 Considering the potential mechanistic effect of statins, a clear understanding of their potential effect in the context of acute TBI is needed. We therefore conducted a systematic review and meta-analysis of randomised controlled trials to assess the effect of statins on functional outcomes and mortality in the management of moderate to severe TBI. ## Methods Our systematic review was conducted in accordance with the recommendations of the Cochrane Handbook for Systematic Reviews and Meta-Analysis.22 We registered the research protocol in the PROSPERO International prospective register of systematic reviews platform (Record ID: CRD42023421227) and reported our results according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines.23 The patients and public were not involved in this work. ### Search strategy We systematically searched Medline (PubMed), Embase, Cochrane Central Register of Controlled Trials and Web of Science databases from their inception to March 2023 for eligible studies. The search strategy was designed with the help of an information specialist using the Peer Review of Electronic Search Strategies (PRESS) guidelines.24 We identified trials using validated strategies to identify randomised controlled trials in Medline and Embase.25 26 The strategy used for Web of Science was adapted from the Cochrane Ear, Nose and Throat Disorders group.27 The Medline search strategy is presented in online supplemental appendix 1. We also conducted backward (by reviewing the reference list of included trials) and forward (by finding trials that cited included trials) citation searching to retrieve any additional relevant publications. In addition, we searched for ongoing and unpublished clinical trials in [http://www.clinicaltrials.gov](http://www.clinicaltrials.gov) and [http://www.controlled-trials.com](http://www.controlled-trials.com) registries. ### Supplementary data [[bmjopen-2024-091971supp001.pdf]](pending:yes) ### Eligibility criteria Randomised controlled trials comparing the use of statins to any comparator (placebo, other intervention or no intervention) in critically ill adult patients (18 years or older) with acute moderate to severe TBI (defined as a Glasgow Coma Scale (GCS) score of 13 or less) were considered for eligibility. We included trials reporting at least one of our outcomes of interest. We considered trials if at least 80% of the study population was 18 years or older and suffered from moderate to severe TBI. No language restriction was applied. ### Study selection and data extraction Citations were reviewed independently by three reviewers (CV, MU and C-JI) for eligibility. The same two reviewers independently extracted data using a standardised, pre-tested data extraction form. Disagreements were resolved by discussion leading to consensus or by a third reviewer (AFT). Following the completion of the screening, the AI tool of DistillerSR was used to verify for screening errors. Retrieved information included characteristics of trials (design, number of participating centres, countries, group sizes), patient characteristics (including initial GCS score), intervention (type of statin, duration and dosage regimen), controls and outcomes. Screening and data extraction were completed using DistillerSR V.2.35 (DistillerSR; 2023, accessed March–December 2023, [https://www.distillersr.com/](https://www.distillersr.com/)). ### Outcome measures Our primary outcome was the Glasgow Outcome Scale (GOS) or the GOS extended (GOSe) score.28–30 The GOS is a 5-point ordinal scale while the GOSe is an updated version on 8 points. A GOS or a GOSe of 1 corresponds to death, and a GOS of 5 or a GOSe of 8 corresponds to a full recovery. We used the common definition of an unfavourable outcome (GOS 1–3 or GOSe 1–4). Secondary outcomes were mortality, intensive care unit (ICU) and hospital length of stay. When multiple assessments over time were reported, we used the latest reported one for our analysis. ### Risk of bias assessment The risk of bias of included trials was assessed independently by two reviewers (CV and C-JI) using the Cochrane Risk of Bias 2 tool.31 Disagreements were resolved through discussions leading to consensus, or by a third reviewer if disagreement persisted (AFT). Trials were categorised as low, unclear or high risk of bias based on the worst score obtained across the six domains. ### Statistical analyses With Review Manager (V.5.4.1, The Cochrane Collaboration, 2020), we used random-effects models with the inverse variance method to calculate risk ratios (RR) for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes, with an associated 95% CI. When needed, we converted medians into means using previously described methods.32 33 We evaluated the presence of statistical heterogeneity using the I2 index.34 We planned subgroup analyses based on TBI severity, presence (or not) of extra-cranial injury (isolated vs multiple trauma), type of statins (lipophilic vs hydrophilic), dosage regimen, duration of the intervention and risk of bias of trials. We based the definition of dosage regimens of statins (high vs low) on the American Hearth Association/American College of Cardiology (AHA/ACC) guidelines to manage cholesterol based on the potency of each different statin.35 We combined the dosage regimen of statins considered to have low to moderate potency in the low-dose category. We evaluated potential publication bias with funnel plots. ### Certainty of evidence and strength of recommendations We evaluated the certainty of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method.36 The final quality of evidence was classified as high, moderate, low or very low for each clinical outcome. Two reviewers (CV and C-JI) performed the classification of GRADE independently. Disagreements were resolved through discussions leading to consensus, or by a third reviewer if the disagreement persisted (AFT). ## Results Our search strategy retrieved 2418 citations from which we removed 155 duplicates. Two trials were initially retrieved in clinical registries, and the full texts were made available during the course of this review.37 38 46 publications were assessed for full-text eligibility (figure 1). Among registered trials, two are mentioned to be completed but are still unpublished,39 40 and one is ongoing.41 Seven trials37 38 42–46 involving a total of 336 patients were included in our analyses. ![Figure 1](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/2/e091971/F1.medium.gif) [Figure 1](http://bmjopen.bmj.com/content/15/2/e091971/F1) Figure 1 Flow diagram of trials. RCT, randomised controlled trial; TBI, traumatic brain injury. ### Characteristics of trials Six of the seven included trials were single centre. Publication date ranged from 2016 to 2023 (online supplemental eTable 1). Five were conducted in Iran42–46 and two in Egypt.37 38 Trials enrolled 20 to 100 patients. Six trials considered patients with moderate and/or severe TBI37 38 42–46 while one enrolled only patients with severe injuries.45 Patients requiring a neurosurgical intervention were excluded in four trials.43–46 Three trials excluded patients who were previously on statins.37 42 45 Atorvastatin was used in four trials37 43 44 46 and simvastatin in the other three.38 42 45 The duration of treatment was 2 days in one trial,37 7 days in another trial,38 10 days in three trials43 45 46 and unreported or unclear in the remaining two.42 44 Five trials were deemed at high risk of bias,38 42–44 one at unclear risk of bias37 44 and one at low risk of bias46 (figure 2). In one trial, the duration of the intervention was not reported, and the methodology was limited.42 In another trial, the intervention was discontinued, and about one-third of the study population was lost to follow-up.41 In one trial, patients who died during the study were excluded from the analysis, and discrepancies in the data reported were observed.45 Finally, in another trial, patients requiring mechanical ventilation at any point during the hospital stay were excluded from the final analysis.38 Funnel plots were not used to explore potential publication bias because of the low number of trials included. ![Figure 2](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/2/e091971/F2.medium.gif) [Figure 2](http://bmjopen.bmj.com/content/15/2/e091971/F2) Figure 2 Risk of bias of trials. ### Data synthesis #### Glasgow Outcome Scale The GOS was reported in 3 trials,38 43 46 representing 144 patients evaluated at 90 or 180 days. In two trials, GOS scores were presented as proportions on the ordinal scale.38 43 In another trial, the mean score of the GOS per group was reported.43 Due to the impossibility of extracting the number of patients with an unfavourable outcome per group, we could not include the data from this trial in our analyses. We found no statistically significant effect of statins on the GOS (RR 0.42; 95% CI, 0.14 to 1.22; two trials; n=84; I2=0%; very low certainty) (figure 3, online supplemental eTable 2). The limited number of trials precluded our ability to conduct subgroup analyses. ![Figure 3](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/2/e091971/F3.medium.gif) [Figure 3](http://bmjopen.bmj.com/content/15/2/e091971/F3) Figure 3 Effect of statins on the incidence of unfavourable neurological functional outcomes (Glasgow Outcome Scale). #### Mortality Data on mortality was available in five trials38 43 46 with a follow-up of 14–180 days. Since no death occurred in two of the five trials, the data of those trials could not be included in the analysis. We observed no statistically significant effect of statins on mortality (RR, 0.59; 95% CI, 0.25 to 1.44; three trials; n=160; I2=0%; very low certainty) (figure 4) (figure 5). No statistically significant effect was observed on mortality for dosage regimen, duration of intervention or the risk of bias of trials (figure 6, online supplemental eTable 2). Other planned subgroup analyses were not performed due to the limited information provided. ![Figure 4](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/2/e091971/F4.medium.gif) [Figure 4](http://bmjopen.bmj.com/content/15/2/e091971/F4) Figure 4 Effect of statins on mortality. ![Figure 5](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/2/e091971/F5.medium.gif) [Figure 5](http://bmjopen.bmj.com/content/15/2/e091971/F5) Figure 5 Secondary outcomes. Random effects models with the inverse variance were used for all analyses. ICU, intensive care unit; WMD, weighted mean difference. ![Figure 6](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/2/e091971/F6.medium.gif) [Figure 6](http://bmjopen.bmj.com/content/15/2/e091971/F6) Figure 6 Subgroup analyses of mortality. #### ICU and hospital length of stay Data from six trials37 38 42 44 46 were included in the analysis of ICU length of stay. We did not observe a statistically significant effect on ICU length of stay with the use of statins (RR, −1.01; 95% CI, −2.31 to 0.28; six trials; n=292; I2=74%; very low certainty) (figure 5). These results were not modified by the severity of the TBI, the dosage regimen, the duration of intervention or the risk of bias. Only one trial reported hospital length of stay46 showing a reduced hospital length of stay with the use of statins (WMD, −3.70; 95% CI, −4.48 to –2.92; one trial; n=60; very low certainty) (figure 5, online supplemental eTable 2). ## Discussion In our systematic review evaluating the use of statins in critically ill patients with acute moderate to severe TBI, we did not observe a statistically significant effect of this intervention on neurological functional outcomes, mortality or ICU length of stay. These observations are, however, based on a limited number of trials, most at high or unclear risk of bias, leading to a very low certainty of evidence. Available data cannot exclude the existence of benefits on patient-centred outcomes, and individual trials all suggest likewise. Our results are somewhat consistent with those from five previous systematic reviews in acute traumatic brain injury since most concluded that statins might be beneficial in TBI patients.13 14 18–20 Nevertheless, these reviews included non-randomised studies, namely, retrospective and prospective cohort studies, which are study designs that could overestimate the potential effect of an intervention. In addition, some of the previous reviews evaluated mortality as the primary outcome, which is not considered the gold standard in TBI research, as a significant proportion of survivors have an unfavourable outcome with severe neurological deficits. Other reviews based their conclusions on laboratory results, which may not be clinically significant and not patient-centred outcomes. Using the GOS as our main outcome allows the evaluation of both mortality and neurological function, an outcome that is patient-centred. The difference between our results and prior reviews, thus, likely reflects the paucity of trials and differences in the outcomes evaluated. Statins have been studied in other neurocritically ill conditions including chronic subdural haematoma,21 47 subarachnoid haemorrhage48 49 and stroke.50 51 The effect of statins following chronic subdural showed no increased risk of recurrence in one42 but an accelerated haematoma resorption, decreased recurrence risk and surgical requirement in the other.21 A recent network meta-analysis also found lower odds of recurrence of chronic subdural haematoma with the use of statins.47 Of note, all three reviews included non-randomised studies. Two systematic reviews in patients with aneurysmal subarachnoid haemorrhage showed a decreased risk of delayed cerebral ischaemia with the use of statins. These reviews, however, showed inconsistent beneficial effects on mortality and no statistically significant difference in functional outcomes.48 49 On the other hand, systematic reviews that investigated the effect of statins on the recurrence of ischaemic stroke in at-risk populations observed a beneficial effect.50 51 Interestingly, the choice of outcomes assessed seemed to largely influence the results as in TBI patients. All reviews conducted in other neurocritically ill populations evaluated mortality as a long-term outcome, an imperfect surrogate outcome of long-term neurological functional outcomes. Trials focusing on mild TBI were excluded since their population is largely different from moderate to severe TBI patients. These patients often do not require hospital admission and almost never require hospitalisation in the ICU. Although they can present long-term symptoms, their evolution is favourable with at most minor disabilities. Therefore, study results including this subtype of patients would not inform clinicians about the management of critically ill TBI patients. Our systematic review has several strengths. First, it was designed to look at patient-centred clinical outcomes to evaluate interventions in critically ill patients with TBI. Second, we considered only randomised controlled trials to limit potential biases and ensure the best level of evidence. Our review also has limitations, largely centred around the limitations of the available body of evidence. The small number of trials identified limits statistical inferences and the extent of analyses that could be performed. Despite a thorough review of the existing evidence, the level of evidence of our findings is limited. Two registered trials are completed but still unpublished ([NCT05551871](http://bmjopen.bmj.com/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05551871&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom), IRCT201109197595). However, their small sample size is unlikely to significantly affect the current findings. The baseline mortality rates observed in the trials included in our review are intriguingly low compared with observational studies.52–58 The application of inclusion/exclusion criteria related to clinical trial enrolment may partially explain the comparatively low mortality observed. Our results must, thus, be interpreted considering the exclusion of patients with the most severe forms of TBI. The duration of the intervention observed in the trials included in our review, ranging from 2 to 10 days, can be considered short by some to appropriately evaluate the effect of statins in this setting. Yet, the main potential effect is likely to be in the first days when the neuroinflammation is at its peak.59–61 Furthermore, the dosage regimens that were used in the trials could also be questioned, as data from studies in other patient populations suggest that the optimal effect is achieved with the highest doses.62 63 ## Conclusion We did not observe a statistically significant improvement in neurological functional outcome in critically ill adult patients with acute moderate to severe TBI. This observation relies on scant data and trials presenting significant risks of biases and, therefore, cannot confidently guide clinical decision-making. The small number of trials, along with the very low certainty of evidence, precludes the ability to draw conclusions and recommendations in this specific patient population. A well-designed and adequately powered multicentre randomised trial evaluating the effect of statins in moderate to severe TBI patients is required. ## Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. ## Ethics statements ### Patient consent for publication Not applicable. ### Ethics approval Not applicable. ## Acknowledgments RZ is supported by the Lyonel G Israels Research Chair in Hematology, University of Manitoba. PL, FL and LM are recipients of salary support awards from the Fonds de Recherche du Québec-Santé. AFT is the chairholder of the Canada Research Chair in Critical Care Neurology and Trauma. ## Footnotes * X @LauzierFrancoi1, @Moore, @alexisturgeon_ * Contributors Substantial contributions to the conception or design of the work or the acquisition, analysis or interpretation of data for the work: CV, MU, M-AG, OC, RZ, DFM, PL, FL, SWE, LM, C-JI and AFT. Drafting the work: CV, MU, M-AG, OC and AFT. Revising it critically for important intellectual content: CV, MU, M-AG, OC, RZ, DFM, PL, FL, SWE, LM, C-JI and AFT. Final approval of the version to be published: CV, MU, M-AG, OC, RZ, DFM, PL, FL, SWE, LM, C-JI and AFT. Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: CV, MU, M-AG, OC, RZ, DFM, PL, FL, SWE, LM, C-JI and AFT. AFT is the guarantor. * Funding This work was funded by a Foundation Scheme grant from the Canadian Institutes of Health Research (CIHR) (#148443). * Competing interests None declared. * Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. * Provenance and peer review Not commissioned; externally peer reviewed. * Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/) This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: [http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/). ## References 1. Dewan MC, Rattani A, Gupta S, et al. n.d. Estimating the global incidence of traumatic brain injury. J Neurosurg130:1080–97. [doi:10.3171/2017.10.JNS17352](http://dx.doi.org/10.3171/2017.10.JNS17352) 2. James SL, Theadom A, Ellenbogen RG, et al. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019;18:56–87. [doi:10.1016/S1474-4422(18)30415-0](http://dx.doi.org/10.1016/S1474-4422(18)30415-0) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/S1474-4422(18)30415-0&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 3. Jacquens A, Needham EJ, Zanier ER, et al. Neuro-Inflammation Modulation and Post-Traumatic Brain Injury Lesions: From Bench to Bed-Side. Int J Mol Sci 2022;23:11193. [doi:10.3390/ijms231911193](http://dx.doi.org/10.3390/ijms231911193) 4. Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017;120:229–43. [doi:10.1161/CIRCRESAHA.116.308537](http://dx.doi.org/10.1161/CIRCRESAHA.116.308537) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImNpcmNyZXNhaGEiO3M6NToicmVzaWQiO3M6OToiMTIwLzEvMjI5IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzIvZTA5MTk3MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 5. Schonbeck U, Libby P. n.d. Inflammation, immunity, and HMG-CoA reductase inhibitors: statins as antiinflammatory agents? Circulation109:II18–26. [doi:10.1161/01.CIR.0000129505.34151.23](http://dx.doi.org/10.1161/01.CIR.0000129505.34151.23) 6. Lokhandwala A, Hanna K, Gries L, et al. Preinjury Statins Are Associated With Improved Survival in Patients With Traumatic Brain Injury. J Surg Res 2020;245:367–72. [doi:10.1016/j.jss.2019.07.081](http://dx.doi.org/10.1016/j.jss.2019.07.081) 7. Mansi IA, English JL, Alvarez CA, et al. Statins in survivors of traumatic brain injury: a propensity score-matched analysis. Brain Inj 2020;34:1367–74. [doi:10.1080/02699052.2020.1802663](http://dx.doi.org/10.1080/02699052.2020.1802663) 8. Wible EF, Laskowitz DT. Statins in traumatic brain injury. Neurotherapeutics 2010;7:62–73. [doi:10.1016/j.nurt.2009.11.003](http://dx.doi.org/10.1016/j.nurt.2009.11.003) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.nurt.2009.11.003&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=20129498&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 9. Wang H, Lynch JR, Song P, et al. Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury. Exp Neurol 2007;206:59–69. [doi:10.1016/j.expneurol.2007.03.031](http://dx.doi.org/10.1016/j.expneurol.2007.03.031) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.expneurol.2007.03.031&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=17521631&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 10. Li B, Mahmood A, Lu D, et al. Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury. Neurosurgery 2009;65:179–85. [doi:10.1227/01.NEU.0000346272.76537.DC](http://dx.doi.org/10.1227/01.NEU.0000346272.76537.DC) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1227/01.NEU.0000346272.76537.DC&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=19574840&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000268265600022&link_type=ISI) 11. Li DD, Huang H, Song JN, et al. The role and mechanism of simvastatin in neuroprotection after diffuse axonal injury. Article Journal of Xi’an Jiaotong University (Medical Sciences) 2014;35:733–9. [doi:10.7652/jdyxb201406003](http://dx.doi.org/10.7652/jdyxb201406003) 12. Wang K-W, Wang H-K, Chen H-J, et al. Simvastatin combined with antioxidant attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. Biomed Res Int 2014;2014:910260. [doi:10.1155/2014/910260](http://dx.doi.org/10.1155/2014/910260) 13. Li M, Huo X, Wang Y, et al. Effect of drug therapy on nerve repair of moderate-severe traumatic brain injury: A network meta-analysis. Front Pharmacol 2022;13:1021653. [doi:10.3389/fphar.2022.1021653](http://dx.doi.org/10.3389/fphar.2022.1021653) 14. Mu S, Fang Y, Pei Z, et al. Outcomes of Preinjury Use of Statins in Patients with Traumatic Brain Injury: A Systematic Review and Meta-analysis. World Neurosurg 2021;152:e266–78. [doi:10.1016/j.wneu.2021.05.083](http://dx.doi.org/10.1016/j.wneu.2021.05.083) 15. Gruenbaum SE, Zlotnik A, Gruenbaum BF, et al. Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury: A Systematic Review of the Clinical Literature. CNS Drugs 2016;30:791–806. [doi:10.1007/s40263-016-0355-2](http://dx.doi.org/10.1007/s40263-016-0355-2) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s40263-016-0355-2&link_type=DOI) 16. Hicks AJ, Clay FJ, Hopwood M, et al. Efficacy and Harms of Pharmacological Interventions for Neurobehavioral Symptoms in Post-Traumatic Amnesia after Traumatic Brain Injury: A Systematic Review. J Neurotrauma 2018;35:2755–75. [doi:10.1089/neu.2018.5738](http://dx.doi.org/10.1089/neu.2018.5738) 17. Clay FJ, Hicks AJ, Zaman H, et al. Prophylaxis Pharmacotherapy to Prevent the Onset of Post-Traumatic Brain Injury Depression: A Systematic Review. J Neurotrauma 2019;36:2053–64. [doi:10.1089/neu.2018.6244](http://dx.doi.org/10.1089/neu.2018.6244) 18. Sultan W, Sapkota A, Khurshid H, et al. Statins’ Effect on Cognitive Outcome After Traumatic Brain Injury: A Systematic Review. Cureus 2021;13:e16953. [doi:10.7759/cureus.16953](http://dx.doi.org/10.7759/cureus.16953) 19. Turner GM, McMullan C, Aiyegbusi OL, et al. Stroke risk following traumatic brain injury: Systematic review and meta-analysis. Int J Stroke 2021;16:370–84. [doi:10.1177/17474930211004277](http://dx.doi.org/10.1177/17474930211004277) 20. Wu L, Zhang SL, Li HY, et al. Effects of statins on mortality and neurologic outcomes in patients with traumatic brain injury: a meta-analysis. Zhonghua Yi Xue Za Zhi 2022;102:813–20. [doi:10.3760/cma.j.cn112137-20210626-01449](http://dx.doi.org/10.3760/cma.j.cn112137-20210626-01449) 21. Monteiro A, Housley SB, Kuo CC, et al. The Effect of Statins on the Recurrence of Chronic Subdural Hematomas: A Systematic Review and Meta-Analysis. World Neurosurg 2022;166:244–50. [doi:10.1016/j.wneu.2022.07.079](http://dx.doi.org/10.1016/j.wneu.2022.07.079) 22. Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions. Cochrane, 2023. Available: [www.training.cochrane.org/handbook](http://www.training.cochrane.org/handbook) 23. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. [doi:10.1136/bmj.n71](http://dx.doi.org/10.1136/bmj.n71) 24. McGowan J, Sampson M, Salzwedel DM, et al. PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement. J Clin Epidemiol 2016;75:40–6. [doi:10.1016/j.jclinepi.2016.01.021](http://dx.doi.org/10.1016/j.jclinepi.2016.01.021) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.jclinepi.2016.01.021&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=27005575&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 25. Glanville JM, Lefebvre C, Miles JNV, et al. How to identify randomized controlled trials in MEDLINE: ten years on. J Med Libr Assoc 2006;94:130–6. [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16636704&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000238639800004&link_type=ISI) 26. Wong S-L, Wilczynski NL, Haynes RB. Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. J Med Libr Assoc 2006;94:41–7. [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16404468&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000234836900006&link_type=ISI) 27. RCT Filters used by Cochrane ENT. Cochrane ENT group. Available: [https://ent.cochrane.org/sites/ent.cochrane.org/files/public/uploads/rct\_filters.pdf](https://ent.cochrane.org/sites/ent.cochrane.org/files/public/uploads/rct_filters.pdf) [Accessed 20 Mar 2023]. 28. Wilde EA, Whiteneck GG, Bogner J, et al. Recommendations for the use of common outcome measures in traumatic brain injury research. Arch Phys Med Rehabil 2010;91:1650–60. [doi:10.1016/j.apmr.2010.06.033](http://dx.doi.org/10.1016/j.apmr.2010.06.033) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.apmr.2010.06.033&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=21044708&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 29. Jennett B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975;1:480–4. [doi:10.1016/s0140-6736(75)92830-5](http://dx.doi.org/10.1016/s0140-6736(75)92830-5) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/S0140-6736(75)92830-5&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=46957&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=A1975V691400005&link_type=ISI) 30. Jennett B, Snoek J, Bond MR, et al. Disability after severe head injury: observations on the use of the Glasgow Outcome Scale. J Neurol Neurosurg Psychiatry 1981;44:285–93. [doi:10.1136/jnnp.44.4.285](http://dx.doi.org/10.1136/jnnp.44.4.285) [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiam5ucCI7czo1OiJyZXNpZCI7czo4OiI0NC80LzI4NSI7czo0OiJhdG9tIjtzOjI2OiIvYm1qb3Blbi8xNS8yL2UwOTE5NzEuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 31. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. [doi:10.1136/bmj.l4898](http://dx.doi.org/10.1136/bmj.l4898) 32. Luo D, Wan X, Liu J, et al. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018;27:1785–805. [doi:10.1177/0962280216669183](http://dx.doi.org/10.1177/0962280216669183) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1177/0962280216669183&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 33. Wan X, Wang W, Liu J, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014;14:135. [doi:10.1186/1471-2288-14-135](http://dx.doi.org/10.1186/1471-2288-14-135) 34. Higgins JPT, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60. [doi:10.1136/bmj.327.7414.557](http://dx.doi.org/10.1136/bmj.327.7414.557) [FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjEyOiIzMjcvNzQxNC81NTciO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvMi9lMDkxOTcxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 35. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082–143. [doi:10.1161/CIR.0000000000000625](http://dx.doi.org/10.1161/CIR.0000000000000625) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1161/CIR.0000000000000625&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=30586774&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 36. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383–94. [doi:10.1016/j.jclinepi.2010.04.026](http://dx.doi.org/10.1016/j.jclinepi.2010.04.026) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.jclinepi.2010.04.026&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=21195583&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 37. Zarief Kamel E, Ibrahem NM, Abu Zeid Yousef H, et al. The anti-inflammatory effects of atorvastatin upon the outcome of traumatic brain injury patients: A randomized-controlled double-blind clinical trial. Egypt J Anaesth 2023;39:715–21. [doi:10.1080/11101849.2023.2246232](http://dx.doi.org/10.1080/11101849.2023.2246232) 38. Hassanin AAM, Ali NS, Abd El Naeem EA, et al. Efficacy of simvastatin in treating patients with traumatic brain injury. Research and Opinion in Anesthesia & Intensive Care 2023;10:46–53. [doi:10.4103/roaic.roaic\_46\_22](http://dx.doi.org/10.4103/roaic.roaic_46_22) 39. Nct. Effects of usage of simvastatin in mild to moderate traumatic brain injury (tbi) patients. 2022. Available: [https://clinicaltrialsgov/show/NCT05551871](https://clinicaltrialsgov/show/NCT05551871) 40. Irct201109197597N. Effect of simvostatin in traumatic brain injury. trial registry record; clinical trial protocol. 2011. Available: [https://trialsearchwhoint/Trial2aspx?TrialID=IRCT201109197597N1](https://trialsearchwhoint/Trial2aspx?TrialID=IRCT201109197597N1) 41. Irct20230627058603N. Rosuvastatin in patients with moderate brain trauma. trial registry record. 2024. Available: [https://trialsearchwhoint/Trial2aspx?TrialID=IRCT20230627058603N2](https://trialsearchwhoint/Trial2aspx?TrialID=IRCT20230627058603N2) 42. Naghibi T, Madani S, Mazloomzadeh S, et al. Simvastatin’s effects on survival and outcome in traumatic braininjury patients: a comparative study. Turk J Med Sci 2016;46:1–5. [doi:10.3906/sag-1404-125](http://dx.doi.org/10.3906/sag-1404-125) 43. Farzanegan GR, Derakhshan N, Khalili H, et al. Effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury; a randomized double-blind placebo-controlled clinical trial. J Clin Neurosci 2017;44:143–7. [doi:10.1016/j.jocn.2017.06.010](http://dx.doi.org/10.1016/j.jocn.2017.06.010) 44. Soltani F, Nassajian N, Tabatabaee K, et al. The Effect of Low-Dose Atorvastatin on Inflammatory Factors in Patients with Traumatic Brain Injury: A Randomized Clinical Trial. Arch Neurosci 2020;7:1–8. [doi:10.5812/ans.106867](http://dx.doi.org/10.5812/ans.106867) 45. Shafiee S, Zali A, Shafizad M, et al. The Effect of Oral Simvastatin on the Clinical Outcome of Patients with Severe Traumatic Brain Injury: A Randomized Clinical Trial. Ethiop J Health Sci 2021;31:807–16. [doi:10.4314/ejhs.v31i4.15](http://dx.doi.org/10.4314/ejhs.v31i4.15) 46. Soltani F, Janatmakan F, Jorairahmadi S, et al. Evaluation of the Effect of Atorvastatin Administration on the Outcomes of Patients with Traumatic Brain Injury: A Double-blinded Randomized Clinical Trial. Anesth Pain Med 2021;11:e117140. [doi:10.5812/aapm.117140](http://dx.doi.org/10.5812/aapm.117140) 47. He C, Xia P, Xu J, et al. Evaluation of the efficacy of atorvastatin in the treatment for chronic subdural hematoma: a meta-analysis. Neurosurg Rev 2021;44:479–84. [doi:10.1007/s10143-019-01218-w](http://dx.doi.org/10.1007/s10143-019-01218-w) 48. Kirkpatrick PJ, Turner CL, Smith C, et al. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol 2014;13:666–75. [doi:10.1016/S1474-4422(14)70084-5](http://dx.doi.org/10.1016/S1474-4422(14)70084-5) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/S1474-4422(14)70084-5&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24837690&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000338483600013&link_type=ISI) 49. Shen J, Shen J, Zhu K, et al. Efficacy of Statins in Cerebral Vasospasm, Mortality, and Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. World Neurosurg 2019;131:e65–73. [doi:10.1016/j.wneu.2019.07.016](http://dx.doi.org/10.1016/j.wneu.2019.07.016) 50. Tramacere I, Boncoraglio GB, Banzi R, et al. Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis. BMC Med 2019;17:67. [doi:10.1186/s12916-019-1298-5](http://dx.doi.org/10.1186/s12916-019-1298-5) 51. Katsanos AH, Lioutas V-A, Charidimou A, et al. Statin treatment and accrual of covert cerebral ischaemia on neuroimaging: a systematic review and meta-analysis of randomized trials. Eur J Neurol 2020;27:1023–7. [doi:10.1111/ene.14196](http://dx.doi.org/10.1111/ene.14196) 52. Peeters W, van den Brande R, Polinder S, et al. Epidemiology of traumatic brain injury in Europe. Acta Neurochir (Wien) 2015;157:1683–96. [doi:10.1007/s00701-015-2512-7](http://dx.doi.org/10.1007/s00701-015-2512-7) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s00701-015-2512-7&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=26269030&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 53. Tagliaferri F, Compagnone C, Korsic M, et al. A systematic review of brain injury epidemiology in Europe. Acta Neurochir (Wien) 2006;148:255–68. [doi:10.1007/s00701-005-0651-y](http://dx.doi.org/10.1007/s00701-005-0651-y) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s00701-005-0651-y&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16311842&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000235737700003&link_type=ISI) 54. Bruns J, Hauser WA. The epidemiology of traumatic brain injury: a review. Epilepsia 2003;44:2–10. [doi:10.1046/j.1528-1157.44.s10.3.x](http://dx.doi.org/10.1046/j.1528-1157.44.s10.3.x) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1046/j.1528-1157.44.s.1.7.x&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=14641556&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 55. Sivco P, Plancikova D, Melichova J, et al. Traumatic brain injury related deaths in residents and non-residents of 30 European countries: a cross-sectional study. Sci Rep 2023;13:7610. [doi:10.1038/s41598-023-34560-7](http://dx.doi.org/10.1038/s41598-023-34560-7) 56. Daugherty J, Waltzman D, Sarmiento K, et al. Traumatic Brain Injury-Related Deaths by Race/Ethnicity, Sex, Intent, and Mechanism of Injury - United States, 2000-2017. MMWR Morb Mortal Wkly Rep 2019;68:1050–6. [doi:10.15585/mmwr.mm6846a2](http://dx.doi.org/10.15585/mmwr.mm6846a2) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.15585/mmwr.mm6846a2&link_type=DOI) 57. Taylor CA, Bell JM, Breiding MJ, et al. Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013. MMWR Surveill Summ 2017;66:1–16. [doi:10.15585/mmwr.ss6609a1](http://dx.doi.org/10.15585/mmwr.ss6609a1) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.15585/mmwr.ss6609a1&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=28301449&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 58. Coronado VG, Xu L, Basavaraju SV, et al. Surveillance for traumatic brain injury-related deaths--United States, 1997-2007. MMWR Surveill Summ 2011;60:1–32. [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=21508921&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 59. Kalra S, Malik R, Singh G, et al. Pathogenesis and management of traumatic brain injury (TBI): role of neuroinflammation and anti-inflammatory drugs. Inflammopharmacology 2022;30:1153–66. [doi:10.1007/s10787-022-01017-8](http://dx.doi.org/10.1007/s10787-022-01017-8) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=35802283&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 60. Morganti-Kossmann MC, Satgunaseelan L, Bye N, et al. Modulation of immune response by head injury. Injury 2007;38:1392–400. [doi:10.1016/j.injury.2007.10.005](http://dx.doi.org/10.1016/j.injury.2007.10.005) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.injury.2007.10.005&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=18048036&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) 61. Schouten JW. Neuroprotection in traumatic brain injury: a complex struggle against the biology of nature. Curr Opin Crit Care 2007;13:134–42. [doi:10.1097/MCC.0b013e3280895d5c](http://dx.doi.org/10.1097/MCC.0b013e3280895d5c) [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/MCC.0b013e3280895d5c&link_type=DOI) [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=17327733&link_type=MED&atom=%2Fbmjopen%2F15%2F2%2Fe091971.atom) [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000244942900004&link_type=ISI) 62. Aggarwal SK, Jiang L, Liu G, et al. Individualized Dose-Response to Statins Associated with Cardiovascular Disease Outcomes. JACC Adv 2024;3:100894. [doi:10.1016/j.jacadv.2024.100894](http://dx.doi.org/10.1016/j.jacadv.2024.100894) 63. Jeong S-M, Shin DW, Yoo TG, et al. Association between statin use and Alzheimer’s disease with dose response relationship. Sci Rep 2021;11:15280. [doi:10.1038/s41598-021-94803-3](http://dx.doi.org/10.1038/s41598-021-94803-3)