In patients who developed ARDS, secondary outcomes did not differ between those who received preoperative statins and those who did not (Table 2). Specifically, there were no significant differences in mortality (7.7% vs 8.8%, P = 0.51), VFD (24 days [15.5–28] vs 25 days [18–27], P = 0.62), ICU length of stay (8.3 days [4.4–15.5] vs 7.1 days [4.1–13.3], P = 0.44), and hospital length of stay (21 days [14–34.3] vs 15 days [11–33], P = 0.21).
The primary propensity score included 5 variables that were measured during the intraoperative period. Because such variables are not known preoperatively, they have the potential to introduce error into the logistic regression. To assess the influence of these variables on the overall study results, a new propensity score was estimated without these variables ([Appendix 2, Supplemental Digital Content 2, http://links.lww.com/AA/A942] estimated equations). The estimated odds ratios for ARDS were 0.93 (95% CI, 0.60–1.43) and 0.87 (95% CI, 0.56–1.34) using the stratified and 1:1 matched analyses, respectively. These results are similar to the primary findings.
In this study, we aimed to better define the association between preoperative statin therapy and postoperative ARDS in patients undergoing high-risk thoracic and aortic vascular surgery. The primary finding was the lack of a protective association between preoperative statin therapy and postoperative ARDS. Notably, this lack of an association appeared robust and was evident in both the unadjusted and propensity-adjusted analyses. In patients who developed postoperative ARDS, patient-important outcomes were not different between those receiving preoperative statins and those who had not.
ARDS has been identified as the most common cause of postoperative respiratory failure and an important cause of perioperative morbidity and mortality.2 Previously identified risk factors for postoperative ARDS have included high-risk surgical procedures (particularly cardiac, aortic vascular, and thoracic), alcohol abuse, chronic obstructive pulmonary disease, diabetes mellitus, and gastroesophageal reflux disease.4 Given the lack of effective therapeutic options for ARDS, interest in exploring preventative therapies in these high-risk groups is high.
The concordance between ARDS pathophysiology and the nonlipid effects of statin therapy make statins a promising potential option for the prevention and/or treatment of ARDS. In animal models of lung injury, simvastatin has been shown to reduce endothelial permeability and lung inflammation across a variety of lung injury mechanisms.18,36–38 In a randomized trial of previously healthy human subjects with lipopolysaccharide-induced lung injury, pretreatment with simvastatin was associated with lower levels of intraalveolar tumor necrosis factor α, as well as a reduction in alveolar neutrophil and protease concentrations.22 However, large-scale randomized clinical trials of statin therapy for the treatment of ARDS have failed to show any measureable benefit of statin therapy in the treatment of established ARDS.24,39 The recently published SAILS study randomized 745 patients to rosuvastatin or placebo within 48 hours of developing sepsis-associated ARDS. The trial was terminated early due to futility after showing no benefit of statin therapy on mortality or other clinical outcomes. Notably, the rosuvastatin group was associated with a greater incidence of renal and hepatic failure.39
Given the discouraging results for statin therapy in the treatment of established ARDS, there is ongoing focus on statins for ARDS prevention. Observational studies evaluating statin therapy have shown mixed results. The results of O’Neal et al.25 suggest that patients taking statins may have reduced risk of developing ARDS. However, this study did not show any effect on patient-centered outcomes such as mortality, ICU length of stay, or VFD. Other observational studies have shown no measureable effects of statins on either ARDS incidence or patient-centered outcomes.15,26 A recently published single-center randomized controlled trial of a small cohort of patients undergoing esophagectomy showed no significant effects in the incidence of ARDS or other patient-important outcomes in patients pretreated with simvastatin.27
Our study has several strengths that deserve mention. It is the first observational study to specifically evaluate whether preexisting statin therapy has any protective effect in the development of ARDS after high-risk surgery. Because the mechanisms underlying ARDS are likely to depend, at least to an extent, on the clinical context surrounding the ARDS episode (e.g., surgery versus sepsis versus aspiration), it is possible that statins may exert differential effects depending on the clinical setting.40 In addition, surgical populations are unique in that the timing of the precipitating factor(s) for ARDS is known in advance. This predictability may facilitate future trials evaluating promising ARDS prevention strategies. To this end, an improved understanding of the potential role of statins in the specific clinical setting of high-risk surgery may provide a template for future clinical trials on statin therapy as an ARDS prevention strategy. This study also used rigorous methods for ARDS adjudication and risk factor ascertainment when compared to prior studies. Our study is the second largest in terms of total patients enrolled and the largest in terms of number of patients taking statins before enrollment. Finally, conclusions drawn from observational studies are inherently limited by measured and unmeasured confounding, bias, as well as missing clinical data. Our study included robust propensity-adjusted analyses that meaningfully addressed baseline imbalances noted in important covariates and allowed an estimation of the error introduced by use of variables not known preoperatively (Table 1). To address missing data, we used sophisticated multiple imputation techniques. In using these strategies, we believe we have substantially enhanced the validity of the study findings.
Importantly, there are also several limitations. As mentioned above, the observational nature of this study creates potential for confounding and bias. While extensive efforts were made to control for bias with a robust propensity-adjusted analysis, potential for residual confounding from variables other than those incorporated in the model remains. The observational study design also precluded the standardization of other important care processes, which could confound the association of interest. A second limitation relates to the determination of the presence of statin therapy. Specifically, due to the retrospective observational nature of this study, formal assessments of medication administration with actual patient interviews were not performed. Rather, we relied on documentation of the medications of interest in the EMR when determining the presence or absence of statin therapy before surgery. It is possible that some patients may have been receiving statin therapy that was not documented in the EMR. Furthermore, it is also possible that some patients with a statin medication listed in the EMR were not actually receiving such therapy before the surgical procedure. In the early postoperative period, 67% of statin takers were restarted on statin therapy. Although stopping statins postoperatively could potentially have masked any protective effect of statin therapy, prior studies have shown no clear consequences of statin cessation in critical illness.41,42 Moreover, any protective effect of statins would most plausibly depend on drug concentrations at the time of the inciting event (i.e., the immediate perioperative period) and consequently not be affected by postoperative statin administration. A third significant limitation is our restriction to patients undergoing high-risk thoracic and aortic vascular surgery. We elected to focus on these specific surgical cohorts due to their known risk for early postoperative ARDS.3,4 As a result of our emphasis on these specific surgical populations, our findings may not generalize to other surgical populations or to medical populations at risk for ARDS. Finally, the study population for this investigation was from a single-center academic medical center. This limited the overall sample size, the number of ARDS events, and consequently the overall precision of the results. This additionally raises concern for referral and institution-specific bias as well as overall generalizability.
In patients undergoing high-risk surgical procedures, preoperative statin therapy was neither associated with a statistically significant reduction in the incidence of postoperative ARDS nor improvements in patient-important outcomes in those who developed ARDS. These results do not support the use of statins as an ARDS preventative measure in patients undergoing high-risk surgery.
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