Participants and pivotal analysis
We reviewed the records of 69 patients treated in the E3 area of the hospital’s ICU from February to March. During the patient selection process, 4 patients were excluded, including 1 patient without severe COVID-19, 1 patient without confirmation of the diagnosis of COVID-19, and 2 patients with incomplete medical records. Therefore, 64 patients were included in the analysis(Fig 1).
Preliminary statistical analysis detected no significant differences in the survival of patients administered chloroquine, broad-spectrum antiviral drugs andantibiotics. However, statins administration was associated with significantly improved survival in patients with severe COVID-19 after adjustment for confounders (Fig 2), and the statins administration cohorthad an adjusted hazard ratio (HR) for mortality of 0.34 compared with the control cohort(p=0.02).
Therefore, we found 11 patients with statins therapy(20mg atorvastatin qd/10mg rosuvastatin qd) prescribed to them in the ICU without previous statins application, while the other 53 were not prescribed with statins therapy. The analysis of the baseline laboratory parameters revealed no significant differences in any of the indexes, indicating that the baseline characteristics were wellbalanced(Table S1). Pearson’s chi-square test did not show any significant differences, which meant that the two groups did not differ other than in the use of statins(Table S2).
Statins and coagulation
Statins may improve prognosis by improving coagulation function
To investigate the effect of statins on patients with severe COVID-19, two-sided t-tests were conducted to determine the differences in biometric variables between the two groups. However, no differences were identified in physiological indexes, blood test results, liver function parameters, metabolic function parameters or cardiac function parameters between the statins group and the control group. However, three key indexes of coagulation, namely, the PT(p=0.003, **), INR(p=0.005, **) and aPTT(p=0.005, **), were significantly less in the statin group than in the control group(Fig 3(A), 3(B)). The differences in these three indexes suggest that the functionality of the intrinsic and extrinsic coagulation pathways was improved in the statin group. In addition, the distribution of the peak values were visualized with density plots in the two groups(Figure 3(C), 3(D)).
Dynamic profiles of coagulation function in the two groups
As the administration of drugs was initiated after the patients were admitted to the ICU, it was possible to investigate the dynamic changes in the biometric indexes. A LOESS model was used to characterize the changes in the PT, INR and aPTT because the distributions of the mean values over time did not adhere to standard distributions. PT trended upward over time in the statin group, while there was no clear trend in the control group (Figure S1(A)). However, in contrast with the stable change over time in the PT, which reflects the function of the extrinsic pathway, the statin group maintained a stable level of the aPTT, which reflects the function of the intrinsic pathway. In contrast, the aPTT rose sharply in the control group over time(Figure S1(B)).
Combination therapy with statins and other drugs could maximize the survival benefit
Further analysis of the effect of the use of combinations of drugs on survival was conducted to identify the treatment strategy that could maximize survival in patients with severe COVID-19. HRs for mortality according to drug combinations are shown in Table 1. The Cox regression analysis showed that the combined use of statins and systemic corticosteroids, anticoagulants or antihypertensive drugs was associated withsignificantly reduced mortality (Figure S2). It can be inferred that these drugs enhanced the anti-inflammatory and anticoagulant effects of statins, leading to improved survival.