This retrospective cohort study examined 2,070 patients treated for COVID-19–related complications in the ICUs in six hospitals affiliated with one healthcare system throughout the first pandemic year. The results suggested that among the multiple COVID-19–related treatments, anticoagulants (i.e., apixaban and enoxaparin) and antiplatelet therapy (i.e., aspirin) were associated with lower in-hospital mortality. Analyses based on propensity score matching suggested that patients treated with apixaban were associated with a 52% lower mortality risk than patients who never received apixaban, patients treated with enoxaparin were associated with a 47% lower mortality risk compared to patients who never received enoxaparin, and patients treated with aspirin were associated with a 43% lower mortality risk compared to patients who never received aspirin. It is worth noting that patients treated with apixaban were older and had more comorbidities than patients who never received apixaban treatment in our study population. Moreover, therapeutic anticoagulants were used for imaging-confirmed venous thromboembolism (i.e., patients were likely sicker). Nevertheless, we still observed an association between apixaban/enoxaparin/aspirin and lower mortality among critically ill COVID-19 patients.
Although abundant treatments were applied to our patients throughout the first pandemic year, our study finds that apixaban, enoxaparin, and aspirin, rather than the previously reported treatments like remdesivir,[7,8] dexamethasone, hydroxychloroquine, convalescent plasma, and famotidine, are associated with lower COVID-19 mortality. In hospitalized COVID-19 patients, four different meta-analyses indicated that venous thromboembolism occurred in 24 to 31% of patients, pulmonary embolism occurred in 12 to 19%, and deep venous thrombosis occurred in 12 to 20%.[13–16] The incidence of venous thromboembolism was much higher in COVID-19 patients admitted to the ICU than those hospitalized on the ward (30% vs. 13%). Patients with severe COVID-19 had an almost four-fold increased risk of venous thromboembolism compared to patients with nonsevere COVID-19. Therefore, the existing evidence advocates a more proactive strategy of systemic anticoagulation therapy in hospitalized COVID-19 patients.
Several studies examined the use of systemic anticoagulants in hospitalized COVID-19 patients.[17,18] A retrospective cohort study involving 4,389 hospitalized COVID-19 patients showed that therapeutic and prophylactic anticoagulation is associated with lower mortality when compared to no anticoagulation therapy. However, that study did not distinguish different anticoagulants and was not explicitly investigating critically ill patients. Another retrospective cohort study involving 3,625 hospitalized COVID-19 patients showed that the prophylactic use of apixaban or enoxaparin was associated with lower in-hospital mortality. The study also showed that apixaban's therapeutic use was associated with lower mortality, although it was not more beneficial than prophylactic use. However, that study was only based on propensity score–matching analysis and only considered the last anticoagulant order in the first 48 h after hospital admission. Therefore, it did not control the confounding exerted by other COVID-19–related treatments, unlike the multivariable analysis used in our study, and it could not tell what would have happened if an anticoagulant had been given after the first 48 h of hospital admission. Moreover, the study involved all hospitalized patients, including patients requiring ICU-level care, and covered a short period (from March 1, 2020, to April 26, 2020; less than 2 months during the early stage of the pandemic); therefore, it may provide a different insight compared to our study, which focuses on ICU patients and spans the entire first pandemic year.
Three international trials compared the effectiveness of therapeutic-dose anticoagulation with heparin versus usual pharmacologic thromboprophylaxis.[3,4] These trials discontinued the enrollment of noncritically ill patients (defined as an absence of critical care-level organ support at enrollment) because of therapeutic anticoagulation's superiority in reducing the need for organ support over 21 days. These trials also discontinued the enrollment of critically ill patients because of therapeutic anticoagulation's futility in reducing the need for organ support over 21 days. These trials did not find an in-hospital mortality difference between different anticoagulation treatments.[3,4] A separate multicenter trial performed in hospitalized COVID-19 patients with elevated D-dimer did not find a difference between therapeutic and prophylactic anticoagulation. However, the result of this trial is challenging to interpret because the primary outcome was defined as a hierarchical composite of time to death, duration of hospitalization, or duration of supplemental oxygen use over 30 days. This trial also did not find a mortality difference between different anticoagulation treatments. Overall, the available evidence showed no mortality difference between therapeutic and prophylactic anticoagulation among hospitalized and critically ill COVID-19 patients. The discrepancy in the results of nonmortality outcome measures among these studies remains to be reconciled.
Although lacking in some details, the current anticoagulation recommendations have primarily focused on the use of enoxaparin. Our findings support this practice. However, our important finding is the robust association between the use of apixaban and lower mortality in critically ill COVID-19 patients, which is consistent with early cohort studies suggesting an association between apixaban treatment and lower mortality in hospitalized COVID-19 patients.[20,21] As a commonly used direct factor Xa inhibitor, apixaban has anticoagulant, anti-inflammatory, and antiviral effects. A previous virology investigation suggested that the inhibition of coagulation factor Xa–mediated cleavage and the subsequent activation of the viral spike protein leads to an impaired fusion of the viral envelope with host cells and, consequently, reduces the infectivity of the SARS virus. This finding offers a mechanism that could explain our observed associations. We note that we did not find an association between the use of rivaroxaban (with a mechanism similar to apixaban) and mortality. The reasons for this finding remain to be elucidated but may be related to the small number of patients who received rivaroxaban treatment (3.4%, 70 of 2,070) in our study population. It should also be noted that the concurrent use of direct oral anticoagulants, including apixaban and antiviral drugs in COVID-19 patients, can lead to an alarming increase in plasma anticoagulant levels and may increase the risk of bleeding.
The association between aspirin treatment and lower COVID-19 mortality identified by our study is consistent with the literature based on large patient cohorts.[25–28] This association was also corroborated by meta-analyses.
This study has several limitations. First, although this cohort study is based on data collected from electronic medical records for all patients treated within a predefined time window across a relatively homogeneous healthcare system, there may still be imprecise information and patient selection bias, especially considering the dramatic toll on the healthcare system caused by the pandemic. Second, our study may be limited by confounding by indication as a retrospective cohort study. Although multivariable analysis and analysis based on propensity score matching were performed, residual bias and a lack of control for unmeasured confounders may still exist. Third, there is a possibility of an immortal time bias or other similar biases related to ignoring differences in timing before treatment because certain medications were not administered until a particular time in the disease course. Fourth, caution is needed when interpreting the data concerning the comparisons of prophylactic and therapeutic anticoagulants with their counterparts because these analyses were not powered to differentiate between different drug doses. Fifth, we conducted a complete case analysis and chose not to impute missing data. Although other approaches dealing with missing data were possible, we excluded patients from specific analyses if the data were missing. Last, as a study based on the experiences of the first pandemic year, the results may not be entirely applicable to future cases, for reasons that include viral mutation, different vulnerable populations, vaccination rates, and the evolution of our knowledge of and measures for treating the disease.
We performed a retrospective cohort study involving all patients treated in a healthcare system's ICUs for COVID-19–related complications throughout the first pandemic year to explore the treatments associated with lower mortality. Consistent with the known hypercoagulability in severe COVID-19, our study showed that the use of apixaban, enoxaparin, or aspirin was independently associated with lower mortality among critically ill COVID-19 patients. The reproducibility of this finding and the ideal dose, timing, and duration of treatment require further elucidation in future studies.
Special thanks go to Soundari Sureshanand, M.C.A., and Richard Hintz, M.S., from the Joint Data Analytics Team at the Yale Center for Clinical Investigation for their proficient and efficient handling of data extraction and reporting.
Support was provided solely from institutional and/or departmental sources.
Anesthesiology. 2021;135(6):1076-1090. © 2021 American Society of Anesthesiologists | Lippincott Williams & Wilkins