In this retrospective, multicenter study, we investigated the impact of statin’s use on the outcome of critically ill patients with COVID-19. Additionally, we evaluated the statins’ effects on the ICU-acquired complications, including safety outcomes. After using cox proportional hazards regression analysis, patients who received statins had a lower 30-day mortality (HR 0.75 (95% CI 0.58, 0.98), P = 0.03) as well as in-hospital mortality (HR 0.69 (95% CI 0.54, 0.89), P = 0.004). Also, patients who received statins had significantly lower hospital-acquired pneumonia and inflammatory markers with no difference in liver injury (P = 0.05).
This study demonstrated that statin therapy in ICU patients with COVID-19 was associated with reduced risks of 30-day and all cause in-hospital mortality. This benefit of statin might be attributed to its pleiotropic anti-inflammatory properties reducing the CPR levels and interleukin-6. These inflammatory markers are known to increase during COVID-19 disease and increase the risk of mortality. In addition, statins have an antioxidant effect and improves endothelial dysfunction, which might help decrease the CV events due to the hyper-coagulopathy status during the course of COVID-19. Theoretically, statins can help reduce the cytokine storm that is usually associated with the poor prognosis of patients infected with COVID-19 . They could also help in up-regulating ACE receptors, thus protecting the lung tissues from the harmful effects of the coronavirus. Similar to our findings, a meta-analysis conducted by Kow et al. reported a significant reduction in fatal or severe COVID-19 disease with the use of statins. However, not all the included studies in this meta-analysis had critically ill patients in their study population. On the other hand, another meta-analysis by Scheen et al. and an observational study by Russo et al. showed that the use of statins was not associated with mortality benefits in patients with COVID-19.[29, 30] This variation from our findings might be because studies were underpowered to detect such a difference[22, 30]. Also, they only included non-severe COVID-19 cases compared to our study that evaluated critically ill patients. A randomized controlled trial (INSPIRATION-statin trial) presented in the American College of Cardiology Virtual Annual Scientific Session (ACC 2021) comparing atorvastatin 20 mg daily vs. placebo showed that initiating statin in critically ill patients with COVID-19 was not associated with improvement in the primary outcome (all-cause death, venous or arterial thrombosis, or treatment with extracorporeal membrane oxygenation) However, we are still awaiting the full report.
We found that the use of statins was not associated with any significant reduction in MVFD or in preventing respiratory failures that require MV eventually. Contrary to our findings, a preliminary study demonstrated a significant reduction in the risk of MV in patients using statin among patients infected with COVID-19 . It is noteworthy that that study included non-ICU patients with COVID-19. Additionally, we observed that critically ill patients who received statins had significantly longer ICU and in-hospital LOS. The higher survival rate could explain the prolonged ICU and hospital LOS in our cohort in the statins group due to several proposed mechanisms such as anti-inflammatory, pleiotropic effects, and antibacterial or antiviral effects[15–18]. Another explanation, the more prolonged ICU and in-hospital LOS may be secondary to higher odds of secondary fungal infection in patients who received statin therapy.
Besides the observed survival benefits in our study with statins therapy use in critically ill patients with COVID-19, we did not report any safety concerns related to statins' side effects or complications. Even though earlier reports from a cohort of 1099 patients with COVID-19 from China showed that up to 39.4% had AST > 40 U/L and 28.1% had ALT > 40 U/L, and most of these elevations occurred in critical COVID-19 cases. We did not find any significant differences in liver injury among the statins and non-statins critically ill groups with COVID-19. Statin showed a good safety profile in our cohort. Still, its use might be hindered by clinicians' reluctance to utilize it in critically ill patients with COVID-19 due to (liver injury, myotoxicity, and rhabdomyolysis-related kidney injury). Therefore, continuing statin therapy as primary or secondary prevention is advisable prior to ICU admission and during ICU stay unless contraindicated.
We believe that our multicenter cohort study is one of few studies that evaluated statins' clinical and safety outcomes in COVID-19 critically ill patients using propensity score matching and multiple regression analysis to minimize the bias. Nevertheless, we also determined some limitations in our study. The retrospective nature of our study may have been affected by missing documentation that could be translated to unmeasured confounders. Also, the medication history use before admission might be affected by limited reconciliation during COVID-19 pandemics. Even though we observed mortality benefits, we did not assess the long-term benefit of statin use after COVID-19 survival. Thus a large randomized controlled trial is needed to investigate the efficacy and safety of statin use in critically ill patients with COVID-19.