Evaluating the Effectiveness of NOAC and LMWHs in Reducing Mortality in Critically Ill Patients with COVID-19

doi:10.21203/rs.3.rs-5033551/v1

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Research Article

Evaluating the Effectiveness of NOAC and LMWHs in Reducing Mortality in Critically Ill Patients with COVID-19

https://doi.org/10.21203/rs.3.rs-5033551/v1

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Background

Severe COVID-19 is associated with increased prothrombotic and inflammatory responses, necessitating effective anticoagulation therapy. Novel oral anticoagulants (NOACs) are being explored as alternatives to low-molecular-weight heparin (LMWH).

Methods

This retrospective cohort study compared the effectiveness and safety of NOACs and LMWH in reducing mortality among 76 critically ill, unvaccinated patients with confirmed SARS-CoV-2 infection. The cohort included 41 patients treated with LMWH and 35 with NOACs during their ICU stay. The primary outcomes focused on mortality, with secondary outcomes including deep vein thrombosis (DVT), bleeding episodes, and transfusion rates.

Results

Baseline characteristics, including demographic data and severity scores, were similar between the groups (mean age: LMWH, 74.5 ± 15.1 years [59% male]; NOAC, 71.6 ± 14.8 years [60% male]). Mortality was significantly greater in the LMWH group (51.21% [95% confidence interval (CI): 36.4–65.7]) than in the NOAC group (20% [95% CI: 10.0–35.9]; p = 0.005), with standardized mortality ratios of 1.61 and 0.71, respectively (p = 0.004). Elevated D-dimer levels are strongly associated with increased mortality risk. DVT occurred in 9.76% of LMWH patients and 5.71% of NOAC patients (p = 0.68). The bleeding and transfusion rates were comparable between the groups.

Conclusions

NOACs were associated with a significantly lower mortality rate than LMWHs in critically ill COVID-19 patients, reflecting an 81% reduced risk of death. These findings highlight the potential advantages of NOACs in managing severe COVID-19 and underscore the need for further research to optimize anticoagulation therapy and improve patient outcomes.

Anticoagulation

COVID-19

Coagulopathy

D-dimer

Thrombosis

Coronavirus disease 2019 (COVID-19) has been diagnosed in more than 774 million individuals and has caused more than seven million deaths as of early 2024 ¹. During the early stages of the pandemic, before vaccination and effective antiviral treatment, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers imbalanced immune responses, systemic inflammation, endothelial dysfunction, and increased thrombotic risk ^2,3. Consequently, COVID-19 was suggested to be the first described viral thrombotic fever (VTF) ⁴, which has since been supported by subsequent research ⁵. Low-molecular-weight heparin (LMWH) has been widely used for thromboprophylaxis and anticoagulation; however, its limited efficacy in preventing venous thrombosis has prompted research on novel oral anticoagulants (NOACs) ⁶. The direct correlation between elevated plasma D-dimer levels (PDDLs) and increased mortality highlights the coagulopathic nature of COVID-19 and supports the need for alternative anticoagulant agents ⁷. Coagulation modifiers, particularly those that inhibit the SARS-CoV-2 main protease (M^pro) (e.g., apixaban), have been identified as potential therapeutic agents ⁸. The successful inhibition of the main protease (Mpro) by ensitrelvir and ibuzatrelvir, both of which are effective against various SARS-CoV-2 variants, including Omicron, has opened new therapeutic avenues by highlighting Mpro as a promising target for antiviral drug development because of its conserved nature and lower mutation rates ^9,10. Although NOACs have been investigated in ICU settings for COVID-19 patients, evidence regarding their safety and efficacy in critically ill patients remains limited ^11,12. These studies did not fully account for the severity of the disease observed in our cohort, which was characterized by increased rates of mechanical ventilation (MV) and vasopressor use. Our study rigorously evaluated the effectiveness and safety of NOACs compared with LMWH in unvaccinated, ICU-admitted patients with COVID-19 during the initial wave of the pandemic. Focusing on mortality rates, thrombotic and hemorrhagic events, and blood (BT) incidence in the hospital setting, our research aimed to augment the current understanding of anticoagulant therapy as a VTF for managing COVID-19.

We hypothesized that, compared with LMWH, NOACs would reduce mortality rates and complications (thrombotic, hemorrhagic events, and BT needs) in unvaccinated ICU-admitted patients with COVID-19. We specifically anticipated that the reduction in mortality would be both statistically and clinically significant, with at least a 10% reduction in mortality rates, as per clinically validated standards ¹³. This distinction between statistical and clinical significance is crucial because it reflects the intervention's real-world impact on patient outcomes ¹⁴.

Study design

In 2023, the Ethics Committee of Pró-Cardíaco Hospital, Rio de Janeiro, Brazil (CAAE: 68235323.3.0000.5533), approved this retrospective, single-center cohort study. The study adhered to the Declaration of Helsinki. The Committee waived the informed consent requirement due to the retrospective nature of the study. All patient data were anonymized and deidentified before analysis. The data were obtained from the Epimed Monitor ICU Database®, a Brazilian clinical data management system for ICUs. The study included patients with COVID-19 admitted between March 23 and December 14, 2020, corresponding to the operational period of a dedicated COVID-19 ICU at our institution.

The full study protocol is available on the Brazilian government research platform, Plataforma Brasil. To access it, visit Plataforma Brasil, select “Buscar Pesquisas Aprovadas,” and search for the research title in Portuguese: “Estudo Retrospectivo, Observacional, Unicêntrico de Duas Terapias Anticoagulantes em Pacientes Críticos Consecutivos com COVID-19 Antes da Era da Vacinação.”

Inclusion criteria

The inclusion criteria for patients were confirmed to be SARS-CoV-2 infection via the GeneXpert platform on nasopharyngeal samples and the need for intensive care unit (ICU) treatment according to the Society of Critical Care Medicine (SCCM) 2016 guidelines ¹⁵.

We employed a two-tier data filtration process to select participants from 88 patients with COVID-19 at a tertiary medical center in Rio de Janeiro. The first tier confirmed 33 patients on apixaban, two on rivaroxaban, and 41 on enoxaparin using electronic health records. The second tier, a manual review, included 76 patients. All eligible participants, aged 18 or older, received consistent anticoagulation or thromboprophylaxis during their ICU stay, with no medication crossover. We excluded patients who had previously begun anticoagulation therapy or who lacked confirmed SARS-CoV-2 testing. Our database contained no patients meeting the exclusion criteria.

Sample size determination and power analysis

A post hoc power analysis was used to assess the study's statistical power, considering the observed effect sizes and data variance. The analysis confirmed the ability of the study to detect significant differences between treatment groups with 80% power at the 5% significance level (Fig. S1).

Outcome measures

The treatment effectiveness was evaluated through mortality rates in hospital and ICU settings. Safety considerations focused on the frequency of bleeding and the notably low incidence of blood clots in VTF patients treated with anticoagulants. Adverse drug reactions were not measured directly but were included in the broader safety analysis.

Enhancement of data collection and analysis

We collected data from electronic health records, including demographic, body mass index (BMI), and chronic disease data. To assess disease severity, we utilized acute clinical scores such as the Sequential Organ Failure Assessment (SOFA) and the Simplified Acute Physiology Score 3 (SAPS3), which measure organ dysfunction and predict mortality risk in patients with critical illness. The modified frailty index-5 (MFI-5) ¹⁶ evaluates patient frailty, an important factor in predicting outcomes in elderly and critically ill populations.

To evaluate thrombotic risk, we implemented the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) Risk Assessment Model with D-dimer (IMPROVE-DD). This validated model categorizes patients into low (0–1), moderate (2–3), and high (4–12) VTE risk levels, helping to minimize selection bias and assess thrombosis risk within and between groups.

We quantified pulmonary involvement using CT lung scores adapted from Bernheim et al. ¹⁷, ranging from 0 (no involvement) to 4 (severe, 76–100% involvement), for assessing lung abnormalities related to patients with COVID-19. Senior radiologists and physicians analyzed these scores to evaluate significant features in affected individuals.

Trained nurses administered NOACs via nasogastric or enteral tubes following established protocols ¹⁸. Dosing was based on clinical indications, ranging from thromboprophylaxis to full anticoagulation, adhering to standard guidelines for the management of patients with severe COVID-19. We recorded the length of hospital stay for all patients to assess the impact of treatments on hospitalization duration. All the data were stored and managed in the Epimed system, ensuring patient confidentiality.

The data collection and analysis approach thoroughly evaluated patient characteristics, disease severity, and treatment outcomes in our study of NOAC therapy versus LMWH use in patients with severe COVID-19. By incorporating multiple validated assessment tools and standardized collection methods, we aimed to provide a robust comparison between these anticoagulation strategies in a critical care setting.

Assessment of Quantitative Variables

A five-tiered stratification method based on the peak PDDL was established using the HemoS1L HS500 assay (Instrumentation Laboratory, Milan, Italy) to enhance risk assessment. PDDL was measured in ng/mL fibrinogen equivalent units (FEUs). The stratification included scores of one (less than two times the upper limit of normal [ULN], two (two times the ULN), three (2.1–3.9 times the ULN), four to 7.9 times the ULN), or five (greater than eight times the ULN). This categorization helps quantify each patient’s coagulation status, providing a foundation for statistical analysis to uncover relationships between the PDDL score and patient outcomes ¹⁹.

On the first day of ICU admission (D1), we used the SAPS3 and SOFA scores to assess patient severity. We then compared the actual mortality with the expected mortality using SAPS3-derived standardized mortality ratios (SMRs). The Modified Frailty Index-5 (MFI-5) evaluates frailty across five domains: diabetes, antihypertensive use, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and functional dependence. Scores ranged from zero (not frail) to five (highly frail). Following the Society of Critical Care Medicine (SCCM) 2016 ICU admission guidelines, we classified patients into four severity priorities: Priority One (intensive treatment), Priority Two (close monitoring), Priority Three (critically ill with limited recovery), and Priority Four (unsuitable for ICU care due to low deterioration risk or irreversible conditions).

Statistical analyses and bias mitigation

The statistical analysis started with the Shapiro‒Wilk test for normality, guiding the choice between parametric (t tests) and nonparametric (Wilcoxon rank-sum, Mann‒Whitney U) tests. Fisher’s exact test was used for categorical data due to the small sample size. Propensity score matching (PSM) minimized selection bias, with full matching chosen for its superior balance, as demonstrated by standardized mean differences and variance ratios. The Cox proportional hazards model was adjusted for covariates, and treatment effects on survival were assessed. The results are displayed in forest plots showing hazard ratios (HRs) and 95% confidence intervals (CIs). Logistic regression analysis further supported these findings. K‒M curves and Z tests were used for survival analysis, and the standardized mortality ratio (SMR) analysis highlighted treatment effectiveness and compared mortality rates. Variance inflation factor (VIF) analysis confirmed that there was no significant multicollinearity. All analyses were conducted using R software (version 2024.04.2 + 764, R Foundation for Statistical Computing, Vienna, Austria), with significance set at p ≤ 0.05.

Availability of Data

The dataset supporting the findings of this study is available in the Mendeley Data repository: Costa, Rubens (2024); "NOACs Versus LMWH in Critically Ill Patients with COVID-19"; and Mendeley Data, V1, doi: 10.17632/cdhv9dgyrk.1.

Patient characteristics and outcomes

The study included 76 participants: 41 in the LMWH group and 35 in the NOAC group. The study period spanned from March 23 to December 14, 2020, during the operation of a dedicated unit for patients with COVID-19 (Fig. 1).

The baseline characteristics were similar, except for arterial hypertension, which was more prevalent in the NOAC group (82.8% vs. 56%, p = 0.02) (Table 1). The median CT lung scores differed significantly (NOAC: 3, LMWH: 2, p = 0.0433) (Figure 2).

Mortality findings

NOAC therapy was significantly associated with reduced in-hospital mortality (20% vs 51.2% in the LMWH group, p = 0.0053). Logistic regression analysis further supported these findings, with an odds ratio of 0.045 (95% CI: 0.0072 to 0.2821, p < 0.001), indicating that NOACs had a strong protective effect (Tables S1, S5). Similarly, ICU mortality was lower in the NOAC group (17.1% vs 39% in the LMWH group, p = 0.03) (Table 2, Fig. 3).

The two groups had similar severity scores (SAPS3, SOFA, IMPROVE-DD, MFI-5, and CCI) (Table 1, Fig. 2). However, the standardized mortality ratio (SMR) analysis revealed that the LMWH group had a 60% greater mortality rate than expected (SMR, 1.60), while the NOAC group had a 29% lower rate (SMR, 0.71) (Z score = 2.812, p = 0.0049) (Table 2, Fig. S4).

Anticoagulation intensity and plasma D-dimer (PDDL) levels

We utilized logistic regression and Cox proportional hazards models to examine the association between anticoagulation intensity (thromboprophylaxis and full anticoagulation) and in-hospital mortality. The analysis revealed no significant effect of intensity on mortality, with a logistic regression coefficient of 0.62522 (p = 0.471) and a Cox model coefficient of 0.316328 (p = 0.6096).

Our findings highlighted that the maximum PDDL is strongly associated with increased mortality risk. Logistic regression analysis revealed a significant log-odds coefficient of 2.10710 (95% CI: 0.2782 to 3.9360, p = 0.023869), corresponding to an odds ratio of approximately 8.23. This indicates a substantial increase in mortality risk (Fig. S2, Table S4).

The Cox proportional hazards model, which focuses on D-dimer scores, supported these findings by revealing a hazard ratio (HR) of 2.0028 (95% CI=1.1409-3.5158, p=0.0156) for elevated D-dimer levels, reinforcing its ability to predict mortality (Figure 5, Table S2).

Polynomial logistic regression confirmed the significant influence of the maximum PDDL on mortality outcomes (p = 0.0015). No significant differences were observed in trends between the LMWH and NOAC groups, suggesting similar treatment effects across different anticoagulation strategies, with an interaction effect p value of 0.39 (Fig. 6).

These results highlight the consistent impact of the PDDL on mortality across various anticoagulation strategies. We employed linear and polynomial regression analyses to assess the maximum PDDL, which demonstrated strong predictive power. The predictive reliability, analyzed as scores and maximum levels, remained consistent regardless of the anticoagulation strategy used (Figure 6) (Table S3).

Other clinical outcomes

The DVT incidence was 5.71% vs. 9.76% in the LMWH group (p = 0.68). Doppler ultrasonography was less common in the LMWH group (39%) than in the NOAC group (62.9%, p = 0.06) (Fig. S3). BT rates were 21.9% in the LMWH group and 5.71% in the NOAC group (p = 0.06), showing a nonsignificant trend. Bleeding episodes occurred in 4.88% of the LMWH group and 5.71% of the NOAC group. In total, 92.7% of patients in the LMWH group and 97.1% of those in the NOAC group were admitted to the ICU at priority levels 1 and 2, respectively (p = 0.69). MV usage (51.2% vs. 40%) and duration (10.2 ± 10.6 days vs. 10.3 ± 7.9 days) did not significantly differ between the groups (Table 2). PSM analysis was performed using full matching and balanced covariates across both groups (Figure 7).

Logistic regression and Cox proportional hazards models

Figure 5 shows the forest plot from the Cox model, which was used to evaluate the impact of clinical and demographic factors on in-hospital mortality among patients treated with NOACs versus LMWH. The analysis revealed a significant reduction in mortality risk for patients receiving NOACs, who were approximately five times less likely to die than were those receiving LMWH, as reflected by an HR of 0.201 (95% CI: [0.059--0.686], p = 0.0103). A higher CCI was also associated with increased mortality (HR: 1.628, 95% CI: [1.060 to 2.499], p = 0.026). A concordance index (C-index) of 0.823 (SE = 0.04) supported the model's robustness, indicating strong discriminative ability. Further statistical validation was performed with the likelihood ratio test (χ²(19) = 40.58, p = 0.003), Wald test (χ²(19) = 28.03, p = 0.08), and score (log-rank) test (χ²(19) = 39.32, p = 0.004) (Table S2).

Univariate analysis revealed no significant differences between the groups regarding septic shock status on day 1, MFI-5 score, IMPROVE-DD score, DVT score, lung CT score, or other clinical variables (Table 1). Overall, these analyses consistently indicated that, compared with LMWH treatment, NOAC treatment significantly reduced the mortality risk in patients with severe COVID-19.

Effect of NOACs versus LMWH on COVID-19 mortality

Our findings indicate a significant association between NOAC therapy and a reduced mortality risk in patients with severe COVID-19 compared with LMWH treatment. Specifically, the odds of mortality for patients treated with NOACs are approximately 75% lower than those for patients treated with LMWHs, corresponding to an odds ratio of 0.2455 (95% CI: 0.0816--0.6698), as derived from contingency table analysis (Tables S1, S5). Logistic regression analysis adjusted for additional variables further corroborated these findings, demonstrating that the mortality risk for LMWH patients was approximately 22 times greater than that for NOAC patients, with an odds ratio of 0.045 (95% CI: 0.0072--0.2821, p < 0.001). Please refer to the supplementary material for a detailed breakdown of these calculations.

Additionally, the Cox proportional hazards model highlighted the significant protective effect of NOACs against hospital mortality, with an HR of 0.201 (95% CI: [0.059 to 0.686], p=0.0103) (Figure 5 and Tables S2, S9). Successful PSM, indicated by reduced standardized mean differences, confirmed that the groups were comparable, minimizing potential confounding factors and strengthening the reliability of our findings. This finding was further supported by the Love plot (Figure 7), which demonstrated minimal confounding in the analysis. To ensure robustness, we conducted a variance inflation factor (VIF) analysis to assess covariate interdependencies within our PSM model (Table S6). The SMR for the LMWH group was 60% greater than that predicted by the SAPS3 score, which aligns with the findings of Quintairos and colleagues ²⁰, who reported an SMR of 1.57 among Brazilian ICU patients with COVID-19 (Fig. S4). Conversely, the SMR for the NOAC group was 0.71, indicating a 55% reduction from its predicted mortality, which is 61.4% lower than that of the Brazilian ICU patient data from the same study. Moreover, the SAPS3 and SOFA scores reported by Correia and colleagues ²¹ were 18% and 25% lower than those reported in our cohort (Table 2), which presented average ICU severity scores higher than the national average.

The interplay between anticoagulation therapy and preexisting conditions

Our study revealed an association between NOAC therapy and decreased mortality via univariate analysis. Hypertension, present in 82.8% of patients treated with NOACs, is typically linked to poorer outcomes in patients with COVID-19. Initially, univariate analysis indicated a significant association between hypertension and reduced mortality; however, this relationship was not confirmed via multivariate analysis (Fig. S2, Table 1). These findings suggest that the protective effect of NOAC therapy may be influenced by multiple factors in a multivariate context, underscoring the complex interaction between preexisting health conditions and treatment outcomes.

Impact on thrombosis and bleeding

Despite concerns about the effectiveness and potential side effects of NOACs, our analysis revealed no significant difference in the incidence of hemorrhagic or thrombotic events between the NOAC and LMWH groups. A recent systematic review suggested that NOACs might be associated with a lower bleeding risk than LMWH in patients who were not critically ill and hospitalized with COVID-19 ²². However, the complex interplay between anticoagulation therapy and COVID-19 underscores the need for further investigation to understand its impact on patient survival outcomes ²³.

The advantage of NOACs over LMWHs stems from their direct inhibition of Factor Xa, which is crucial in thrombin regulation. This blockade prevents the conversion of prothrombin and directly reduces thrombin concentrations, minimizing clot formation. Unlike LMWH, which requires antithrombin and acts indirectly, NOACs can penetrate thrombi, offering a significant benefit, particularly during severe inflammatory states where antithrombin levels may vary. Additionally, NOACs offer benefits such as oral administration, predictable pharmacokinetics, and no need for routine laboratory monitoring, increasing their clinical utility.

Although COVID-19-induced coagulopathy is similar to severe sepsis, it is characterized predominantly by thrombotic rather than hemorrhagic occurrence ⁴. Fatal outcomes frequently arise from extensive fibrin deposition and significant thrombin generation, particularly within the lung microvasculature ⁵. This leads to acute respiratory distress syndrome, coagulopathy, vascular device thrombosis, and occlusive events such as stroke and limb ischemia. Our ICU cohort consisted of patients with severe COVID-19, as reflected by higher-than-average ICU severity scores in Brazil ²⁰.

Bioavailability issues in ICU patients receiving vasopressors

The frequent use of vasopressors, which affects more than half of the patients on their first ICU day (53%, Table 1, Fig. S5), suggests a potential underestimation of their effect on LMWH bioavailability ²⁴. Hemodynamic instability in patients with severe COVID-19 may further contribute to the observed increase in mortality in the LMWH group. Bioavailability is particularly challenging under conditions where hypoxia exacerbates thrombosis through hypoxia-inducible pathways. Moreover, vasopressors, including protein C and thrombomodulin, interact with endothelial and coagulation pathways, complicating the breakdown of prothrombinase and tenase complexes and potentially increasing thrombin levels ⁴. Additionally, the formation of neutrophil extracellular traps in severe COVID-19 amplifies thrombo-inflammatory responses ²⁵. Consequently, ICU patients receiving vasopressors may require tailored dosing or alternative methods of LMWH administration to optimize therapeutic effectiveness ²⁶.

Prognostic value of D-dimer

The PDDL in patients with severe COVID-19 often exceeds that observed in patients with community-acquired pneumonia and has significant prognostic value ²⁷. Specifically, D-dimer concentrations above twice the ULN have been linked to poor outcomes in advanced COVID-19 patients, frequently indicating increased rates of intubation and mortality. In our subanalysis, we found that the initiation of mechanical ventilation (MV) was strongly correlated with increased mortality, particularly at higher PDLLs (Fig. S6), suggesting that a more significant burden of comorbidities is associated with higher mortality.

Our findings align with a recent Polish randomized study, which demonstrated that anticoagulant therapy, particularly unfractionated heparin, was associated with a lower incidence of MV than LMWH ²⁸. Furthermore, our Cox proportional hazards model—adjusted for severity and comorbidities via propensity score matching (PSM)—revealed a significant increase in mortality risk with increasing PDDL. Specifically, each doubling of the PDDL was associated with a more than twelvefold increase in mortality risk, as shown by our polynomial logistic regression analysis (HR=12.59, 95% CI=4.03–21.15], p=0.00178) (Fig. 6, Table S3). This robust association underscores the critical importance of monitoring the PDDL as a prognostic indicator.

In support of this, the literature has consistently linked high PDDL scores to increased mortality in patients with COVID-19. Ranucci and colleagues ²⁹ reported critical hemostatic disturbances in nonsurvivors, including increased thrombin and fibrin turnover, reduced fibrinolysis, and enhanced baseline fibrinolysis inhibition, as evidenced by elevated plasminogen activator inhibitor-2/plasmin‒antiplasmin ratios. Thrombin generation patterns differ distinctly between survivors and nonsurvivors, contributing to severe thrombo-inflammatory responses and microvascular damage, as further evidenced by elevated PDDL. These findings highlight the prognostic importance of D-dimer levels and support the integration of NOACs into comprehensive strategies for managing coagulopathy in patients with severe COVID-19.

Anticoagulation Strategies Amidst Uncertain Evidence

Our study was conducted during the pandemic's early stages before establishing standardized treatment protocols, such as antivirals, vaccines, corticosteroids, and interleukin-6 inhibitors ^30,31. Consequently, our findings provide unique insights into the effectiveness of anticoagulation therapy within an evolving therapeutic context. The absence of these treatments emphasizes the importance of our results and highlights the potential of NOACs when broader treatment options are unavailable. Moreover, as emerging SARS-CoV-2 variants that evade immunity may lead to new waves of severe infections requiring ICU admission, these findings underscore the need for prospective trials within evolving therapeutic standards to validate and refine anticoagulation strategies for severe COVID-19, contributing to global efforts to improve patient outcomes (Table S10).

The need for personalized anticoagulation strategies, informed by the latest research and tailored to individual risk profiles, remains critical for managing conditions characterized by significant inflammatory responses, including severe COVID-19. Billett et al.¹¹ found that early initiation of apixaban or enoxaparin within 48 hours of hospital admission significantly reduced mortality, with apixaban showing effectiveness comparable to that of enoxaparin. Stratification by PDDL indicated that higher levels were associated with increased mortality, highlighting the benefits of anticoagulation, particularly in patients with a PDDL above 10 µg/mL, without increasing the need for transfusion.

Previous research has highlighted the benefits of therapeutic anticoagulation in noncritically ill patients. However, the evidence concerning the efficacy of LMWH or unfractionated heparin in critically ill COVID-19 patients is mixed ^32,33. Our cohort study revealed a preference for apixaban (94.3%, 33 out of 35 patients) over rivaroxaban (5.7%, 2 out of 35 patients) among critically ill patients receiving NOACs, despite limited evaluations of NOACs in patients with severe COVID-19 ^11,12^, and established the benefits of LMWH in treating COVID-19-associated coagulopathy. The pronounced use of apixaban suggested a shift in therapeutic strategies, potentially influenced by drug safety profiles ¹², individual patient considerations, or emerging evidence not captured in earlier studies. As reported by Gloeck et al. ³⁴, the importance of high-quality randomized controlled trials (RCTs) for comparing different anticoagulation intensities in hospitalized COVID-19 patients has been emphasized, highlighting the critical need for clinicians to carefully consider the risk‒benefit ratio in clinical decision-making.

Our findings align with existing research that links elevated PDDL (scored according to our methodology) with increased mortality risk in patients with COVID-19, demonstrating that this risk is consistent across different anticoagulation intensities (Fig. S2). In contrast to the COVID-19-PREVENT trial ³⁵, which excluded patients requiring ICU admission at randomization, our retrospective study uniquely examined only ICU-admitted patients, a focus rarely observed in COVID-19 research. Similarly, the HEP-COVID trial ³⁶ advocated intensive anticoagulation in patients with PDDL (> 4× ULN) or significant coagulopathy.

Despite the favorable safety profile of apixaban, the CHEST guidelines³⁷ for managing COVID-19 in critically ill patients do not fully endorse its therapeutic use. Apixaban should potentially be considered for reducing end-organ failure and death in noncritically ill patients, but its efficacy in critically ill patients is unclear because of a lack of robust evidence.

DVT incidence analysis

In our study, the incidence of DVT was 9.8% in the LMWH group and 5.7% in the NOAC group among ICU-admitted COVID-19 patients (Figure S3). These rates are significantly lower than the 25% incidence reported by Cui and colleagues and less than the 12.7% incidence (95% CI: 8.7--17.5) noted in a meta-analysis by Kollias and colleagues ³⁸.

Although our study focused on occurrence, the 7.7% incidence of VTE in non-ICU patients reported by Mansory and colleagues ³⁹ highlights the distinct risk profiles and underscores the need for precise VTE management strategies across different care settings.

Chaves and colleagues ⁴⁰ explored the dual role of apixaban as an anticoagulant and potential antiviral agent because of its noncompetitive inhibition of virus replication. However, the efficacy of therapeutic doses of apixaban for viral inhibition has not been determined ⁴¹.

This study highlights the need for standardized anticoagulation protocols to manage severe COVID-19 effectively, as shown by the lower DVT rates in our study (Fig. S3). The challenges of selecting optimal treatment strategies—marked by high rates of undetected DVT and significant autopsy ⁴² findings—underscore the critical importance of standardizing these practices. Variability in anticoagulation protocols, antithrombin levels, and anti-Factor Xa measurements complicates heparin use, hindering a deeper understanding of therapeutic outcomes in COVID-19 treatment. Despite the high incidence of hypertension (82.8%) in our cohort, mortality rates were lower among patients treated with NOACs. Although univariate analysis suggested an association between hypertension and reduced mortality, this was not confirmed by multivariate analysis (Fig. S2, Table 1), suggesting that the protective effects of NOAC therapy may be influenced by other variables in the multivariate model, illustrating the complex interplay between preexisting conditions and treatment outcomes in patients with COVID-19.

Study limitations

The interpretability of the study is limited by its retrospective design, single-center setting, and short in-hospital follow-up period. Although the moderate sample size was sufficient to detect clinically significant differences, as demonstrated by our post hoc analysis, this may restrict the generalizability of our findings.

A key limitation is the absence of thrombin generation tests and anti-factor Xa measurements in the LMWH group. These findings provide evidence of the pharmacological effect of LMWH and insights into its efficacy in treating severe COVID-19. Without these measurements, we cannot determine whether the poorer outcomes in the LMWH group were due to inadequate anticoagulant effects from antithrombin deficiency (which is crucial for the action of LMWH) or other factors related to COVID-19. This limitation hinders our ability to explain the mechanism behind the observed differences in mortality between the NOAC and LMWH groups.

Variability in clinical practices among physicians and over time may have influenced outcomes, particularly given the early pandemic context with evolving treatment protocols. The unique characteristics of our study population, including disease severity and demographic data, limit the generalizability of our findings to other contexts.

Despite the use of propensity score matching, unmeasured confounding factors may have influenced the results. The short follow-up period limited our ability to assess long-term outcomes and delayed adverse effects. Reliance on electronic health records and manual data extraction could have introduced inaccuracies, particularly regarding comorbidities and treatment adherence.

The lack of randomization hinders causal inferences between NOAC and LMWH use. Potential underreporting or misclassification of adverse events and dosing variability also challenge our findings. The unique nature of our study in anticoagulation research for patients with severe COVID-19 limits direct comparisons with others, emphasizing its novelty and the need for further validation.

Prospects

As COVID-19 evolves with widespread vaccination, future research must address key areas. It is crucial to investigate the efficacy of novel oral anticoagulants (NOACs) in patients with severe COVID-19 who experience vaccine breakthrough infections or compromised immunity, as these patients may remain at high risk for severe outcomes. Understanding the impact of evolving SARS-CoV-2 variants, especially oral direct factor Xa inhibitors, on anticoagulation treatments is essential. Variants such as KP.3 and LB.1, known for increased transmissibility and immune evasion, challenge current protocols (Table S10). Future studies should expand in scale and diversity, incorporating genomic surveillance to track strains. These studies should aim to determine how different variants affect anticoagulation therapy efficacy and whether dosing or drug selection adjustments are necessary.

Lessons from managing coagulopathy in patients with COVID-19 apply to other severe infections with elevated thrombotic risk, such as sepsis. Comparative studies between NOACs and LMWHs could provide insights into broader applications of anticoagulation therapies in critical care. The success of NOACs in critically ill patients with severe thromboinflammatory conditions underscores their potential for wider use ⁴³.

Emerging SARS-CoV-2 variants that evade immunity may lead to new waves of severe infections requiring ICU admission ⁴⁴. Therefore, prospective trials within evolving therapeutic standards are needed to validate and refine anticoagulation strategies. These trials should consider the efficacy of NOACs against evolving variants and their potential synergistic effects with other treatments ⁴⁴^. Furthermore, developing personalized protocols based on individual risk factors in patients with COVID-19, biomarkers, and genomic data of the infecting strain should be prioritized ⁴⁵.

Long-term studies on the efficacy and safety of NOACs in preventing severe COVID-19 and their role in preventing and managing post-COVID-19 complications are necessary. Economic evaluations of the expanded use of antibiotics for severe infectious diseases and strategies to address implementation challenges in diverse healthcare settings will be crucial for translating research into clinical practice.

By pursuing these research directions, we can address the dynamic nature of COVID-19 while expanding our understanding of anticoagulation strategies for severe infectious diseases. This approach could revolutionize thrombotic risk management in critical care, improving outcomes for patients with evolving viral threats and adapting to changing therapeutic landscapes.

This study confirms the initial hypothesis by demonstrating the effectiveness and safety of NOACs in treating patients with severe COVID-19. Compared to LMWHs, NOACs were significantly associated with lower hospital mortality, with an 81.31% reduced risk of death. These findings emphasize the potential of these devices for managing patients with severe COVID-19, despite increased pulmonary involvement and a greater incidence of hypertension in the NOAC group. The persistence of thromboembolic events, regardless of anticoagulation intensity, highlights the pronounced prothrombotic tendency of COVID-19, supporting its classification as a VTF. These findings emphasize the urgency of further research into anticoagulation therapies to optimize treatment and improve outcomes for patients with severe COVID-19.

COVID-19

coronavirus disease 2019

ICU

intensive care unit

LMWH

low-molecular-weight heparin

NOACs

novel oral anticoagulants.

ACKNOWLEDGMENTS

We wish to extend our heartfelt appreciation to Professors Gonzalo Bello Bentacor, PhD; José Mengel, PhD; Marcelo Pelajo-Machado, PhD; Marcelo Pinto, PhD; Marco Aurélio Martins, PhD; Marcelo Pinto, PhD; Patricia Bozza, PhD; and Tatiana de Arruda Campos Brasil de Souza, PhD, as well as to the honored late Rodrigo Correia, PhD (in memoriam), all esteemed members of FIOCRUZ. Their outstanding mentorship and insightful expertise have been pivotal in guiding us through the conceptualization and characterization of viral thrombotic fever during the challenging backdrop of the COVID-19 pandemic. We acknowledge the substantial and invaluable contributions that have significantly shaped our academic and research endeavors during these historical attempts, with the utmost respect and gratitude. Furthermore, we extend our deepest gratitude to the entire intensive healthcare team at Pró-Cardíaco Hospital for their relentless efforts during the pandemic. Their dedication and commitment in those challenging times have been truly inspiring and are greatly appreciated.

FUNDING

This work was supported by the National Council for Scientific and Technological Development (CNPq) [grant number 401700/2020-8] and by the Carlos Chagas Filho Foundation for Research Support in the State of Rio de Janeiro (FAPERJ) [grant numbers E-26/211331/21 and E-26/201029/2021].

CONFLICT OF INTEREST

None declared.

AUTHORSHIP DETAILS

RC Costa-Filho directed the conceptual framework, design, manuscript writing, creation of R Studio graphs, and data analysis of the study. AJ Oliveira was responsible for the CT scan analysis and development of the CT lung score. F. Saddy coordinated patient care during hospitalization and contributed to the data analysis. JLF Costa and MINH Barbosa oversaw the CRRT data management and analysis. MS Azevedo, DF Cerqueira, VHA Gualberto, and MINH Barbosa focused on the data collection and recorded the examinations through the Epimed System. AM Da-Cruz contributed to the manuscript through critical revisions. MA Horta engaged in the statistical review and significance testing within R scripts. JPG Leite made substantial revisions to the manuscript and provided critical intellectual input. HC Castro-Faria-Neto was pivotal in the study's creativity, design, writing, and meticulous review, ensuring the project's coherence and rigor.

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Tables 1 and 2 are available in the Supplementary Files section.

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Evaluating the Effectiveness of NOAC and LMWHs in Reducing Mortality in Critically Ill Patients with COVID-19

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Abstract

Background

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INTRODUCTION

METHODS

Study design

Inclusion criteria

Sample size determination and power analysis

Outcome measures

Enhancement of data collection and analysis

Assessment of Quantitative Variables

Statistical analyses and bias mitigation

Availability of Data

RESULTS

Patient characteristics and outcomes

DISCUSSION

CONCLUSIONS

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