Prophylactic Anticoagulation and Thrombosis in Hospitalized Patients with Clinically Stable COVID-19 at Admission: From the Practice-Based Observational Study

Objectives: The potential benefit of routine prophylactic anticoagulation for all hospitalized patients with clinically stable coronavirus disease 2019 (COVID-19) is still controversial. Method: The CLOT-COVID Study was a multicenter observational study enrolling 2894 consecutive hospitalized patients with COVID-19. The current study population consisted of 1738 hospitalized patients with mild COVID-19 at admission not requiring oxygen administration, who were divided into 2 groups: patients with prophylactic anticoagulation (n = 326) and those without (n = 1412). Results: Patients with prophylactic anticoagulation had more severe status of the worst severity of COVID-19 during hospitalization compared with those without (mild: 38% versus 82%, moderate: 55% versus 17%, and severe or death at discharge: 6.4% versus 0.7%, P <0.001). During hospitalization, 8 patients (0.5%) developed thrombosis, and the incidences of thrombosis were numerically higher in patients with more severe status of worst severity of COVID-19 during hospitalization (mild: 0.2%, moderate: 1.2%, and severe or death at discharge: 3.2%). Conclusions: Among hospitalized patients with clinically stable COVID-19 at admission, patients who did not worsen in COVID-19 severity after admission rarely developed thrombosis, although patients with worsening of COVID-19 severity after admission more often received prophylactic anticoagulation and might have a higher risk of thrombosis.


Introduction
The coronavirus disease 2019 (COVID-19) has become a huge threat all over the world, 1,2) which has been reported to cause cardiovascular complications including thrombosis. 3,4)Based on the potential benefit of prophylactic anticoagulation for prevention of thrombosis and worsening of disease severity, several international statements recommend prophylactic anticoagulation for all hospitalized patients with COVID-19. 5,6)However, the risk of thrombosis in patients with COVID-19 has been reported to vary widely according to patient characteristics including disease severity of COVID-19, and optimal prophylactic anticoagulation strategies could be still controversial. 7,8)ecause patients with severe status of COVID-19 have been reported to be at a higher risk of thrombosis, prophylactic anticoagulation for patients with clinically unstable COVID-19 could be useful to improve clinical outcomes. 9,10)][13][14] However, the potential benefit of prophylactic anticoagulation for all hospitalized patients with clinically stable COVID-19 including those who do not require oxygen administration might be a matter of active debate.Actually, a recent study has failed to show a potential benefit of antithrombotic therapy for symptomatic clinically stable outpatients with COVID-19. 15)Because the majority of patients with COVID-19 are currently on clinically stable status, the optimal prophylactic anticoagulation strategy for those patients is becoming more clinically relevant, although there has been still limited data on the issue.Thus, the current study aimed to overview the current status of prophylactic anticoagulation and thrombosis in hospitalized patients with clinically stable COVID-19, using a large observational database of patients with COVID-19 in Japan.

Study population
The CLOT-COVID Study (Thrombosis and Anticoagulation Therapy in Patients with COVID-19 in Japan Study: UMIN000045800) was a multicenter retrospective cohort study enrolling 2894 consecutive hospitalized patients with COVID-19 at 16 centers in Japan between April 2021 and September 2021.The details of the study were reported previously. 16,17)The relevant review boards or ethics committees in all participating centers (Supplementary Appendix 1; all supplementary files are available online) approved the research protocol.
In the current study, after excluding 927 patients with moderate COVID-19 at admission who required oxygen administration and 229 patients with severe COVID-19 at admission who required mechanical ventilation or extracorporeal membrane oxygenation (ECMO), 10,18) the current study population consisted of 1738 hospitalized patients with mild COVID-19 at admission who did not require oxygen administration (Fig. 1).The current study population was divided into 2 groups: patients with prophylactic anticoagulation during hospitalization and those without, and we compared patient characteristics and clinical outcomes during hospitalization between the 2 groups.

Definitions for patient characteristics
Prophylactic anticoagulation was defined as the usage of anticoagulants during the hospitalization except for their usage for the treatment of thrombosis, including unfractionated heparin, low-molecular-weight heparin, direct oral anticoagulants, and warfarin.Worst severity of COVID-19 during hospitalization was classified into 3 groups: mild status (no worsening after admission), moderate status who required oxygen administration, and severe status who required mechanical ventilation or ECMO, or death at discharge.The detailed definitions of other patient characteristics are described in the Supplementary Appendix 2.

Clinical endpoints
The primary endpoint was thrombosis during the hospitalization, which included venous thromboembolism (VTE), ischemic stroke, myocardial infarction, systemic arterial thromboembolism, and other systemic thrombosis.VTE was defined as pulmonary embolism and/or deep vein thrombosis that was objectively confirmed by imaging examinations or by autopsy.Ischemic stroke was defined as stroke either requiring or prolonging the hospitalization with symptoms lasting more than 24 hours.Myocardial infarction was defined in accordance with the universal myocardial infarction guidelines. 19)he secondary endpoints were major bleeding and allcause death during hospitalization.Major bleeding was diagnosed as International Society of Thrombosis and Hemostasis (ISTH) major bleeding. 20)

Statistical analysis
Categorical variables were presented as numbers and percentages, which were compared with the chi-square test when appropriate; otherwise, a Fisher's exact test was used.Continuous variables were presented as mean and standard deviation or median and interquartile range based on their distributions, which were compared using the Student's t-test or the Wilcoxon rank-sum test.The clinical endpoints were presented as numbers of events and percentages with the 95% confidence intervals (CIs).Furthermore, we evaluated clinical endpoints by stratified analysis according to the worst severity of COVID-19 during hospitalization.All statistical analyses were performed using JMP version 14.0 software (SAS Institute Inc., Cary, NC, USA).All reported P-values were 2-tailed, and P-values less than 0.05 were considered significant statistically.

Patient characteristics
Among 1738 hospitalized patients with mild COVID-19 at admission, 326 patients (19%) received prophylactic anticoagulation during hospitalization and 1412 patients (81%) did not.Patients with prophylactic anticoagulation during hospitalization were older (56.7 years versus 47.0 years, P <0.001), more often men (70% versus 60%, P <0.001), and had a higher body weight and body mass index (71.2kg versus 66.1 kg, P <0.001 and 26.1 kg/m 2 versus 24.4 kg/m 2 , P <0.001) than those without (Table 1).The median D-dimer level at admission was higher in patients with prophylactic anticoagulation than that in those without (0.8 μg/mL versus 0.5 μg/mL, P <0.001).Patients with prophylactic anticoagulation during hospitalization more often had several comorbidities including hypertension, diabetes mellitus, heart disease, and active cancer.
Patients with prophylactic anticoagulation during hospitalization had more severe status of the worst severity of COVID-19 during hospitalization compared with those without (mild: 38% versus 82%, moderate: 55% versus 17%, and severe or death at discharge: 6.4% versus 0.7%, P <0.001) (Table 1).Most of prophylactic anticoagulation was conducted with anticoagulants of a prophylactic dose, and 60% and 22% of prophylactic anticoagulation was unfractionated heparin of a prophylactic dose and low-molecular-weight heparin of a prophylactic dose, respectively (Table 1).

Discussion
The main findings of the current study are as follows: 1) Patients who worsened in COVID-19 severity after admission more often received prophylactic anticoagulation during hospitalization, 2) the incidence of thrombosis was numerically higher in patients who worsened in COVID-19 severity after admission than that in those who did not, and 3) a minority of patients without worsening of COVID-19 severity developed thrombosis, who showed relatively high D-dimer levels at admission.
Thrombosis is reported to be one of common complications in patients with COVID-19 including thrombus formation in large vessels as well as in microvasculature, which has been described as COVID-19-associated coagulopathy. 21)COVID-19-associated coagulopathy was reported to cause in-situ thrombosis in large and small vessels of lung at the capillary-alveolar interface, which might contribute to the worsening of respiratory failure. 22,23)Thus, there has been thought to be potential benefit of prophylactic anticoagulation for patients with COVID-19.Actually, several observational studies reported that anticoagulation therapy during hospitalization was associated with better clinical outcomes, including improved survival in hospitalized patients with COVID-19. 24,25)Based on these previous reports, several current guidelines recommend prophylactic anticoagulation for all hospitalized patients with COVID-19. 5,6)On the other hand, the threshold for admission to the hospital could widely vary according to each region and country due to a different medical system and resource availability, as well as a different study period.In Japan, the hospitalization for COVID-19 has not been limited to only patients with severe status of The current study also showed that the risk of thrombosis might become higher in patients who worsened in COVID-19 severity after admission.Considering a higher risk of thrombosis in patients with more severe status of COVID-19, 9,10) initiation of prophylactic anticoagulation for patients with clinically stable COVID-19 at admission could be useful if they worsened in COVID-19 severity after admission.Because the COVID-19 severity could be changed dynamically through the course of treatment even in clinically stable patients at admission, 1,26) clinicians might have to be notified that the risk of thrombosis could be changed according to the status of COVID-19 severity after admission.In line with the current study, a previous study reported that 3.3% of clinically stable outpatients with COVID-19 became clinically unstable during the follow-up period and a few of them died due  to COVID-19-related respiratory failure. 15)These results might suggest the importance of close medical follow-up even in patients with initially clinically stable COVID-19.
Although several current guidelines recommend prophylactic anticoagulation for all hospitalized patients with COVID-19, 5,6) the necessity of routine prophylactic anticoagulation for all hospitalized patients with clinically stable COVID-19 could be controversial.There have been limited studies evaluating prophylactic anticoagulation specifically for hospitalized patients with clinically stable COVID-19.The recent randomized clinical trial evaluating outpatients with COVID-19 has reported that prophylactic anticoagulation compared with placebo did not reduce the major adverse outcomes in patients with clinically stable COVID-19, 15) suggesting no benefit of prophylactic anticoagulation for clinically stable outpatients.The current study showed that a minority of patients without worsening of COVID-19 severity after admission developed thrombosis, which could suggest a quite low risk of thrombosis in patients with clinically stable COVID-19.The current study revealed that among 1280 patients with clinically stable COVID-19 during hospitalization, only 2 patients (0.2%) developed thrombosis.One of clinical features in these patients was relatively high D-dimer levels at admission of 4.6 μg/mL and 15.0 μg/mL.In patients with clinically stable COVID-19, D-dimer levels at admission might be important for risk assessment for development of thrombosis beyond the COVID-19 severity.Although it could be difficult to estimate the effect of prophylactic anticoagulation for these patients, the current results could be useful for clinicians because there was no signal of concerns for the management strategy without prophylactic anticoagulation for these low-risk patients.The current study could challenge the potential benefit of routine prophylactic anticoagulation for all hospitalized patients with clinically stable COVID-19.Considering the risk of bleeding related to prophylactic anticoagulation, further randomized clinical trials should be warranted to investigate the potential benefit and harm of prophylactic anticoagulation for hospitalized patients with clinically stable COVID-19.

Study limitations
The current study had several limitations.First and most importantly, the current study was an observational study, which could show only association, not causality.Especially, causal relationship between the prophylactic anticoagulation and development of thrombosis was unclear.Overlapping risk factors for thrombosis and COVID-19 severity could be a potential mechanism for the current results.In addition, the therapeutic decision-making including prophylactic anticoagulation was left to the discretion of the attending physicians, which could have a certain influence on clinical outcomes.Second, the absolute number of clinical events was relatively small, although it was derived from a large observational database of patients with COVID-19.We could not conduct the statistical adjustment including the multivariable analyses to take baseline imbalances between the groups into consideration.Third, the current study evaluated only clinical outcomes during hospitalization.Thus, we could not discuss the risk of thrombosis after discharge.Fourth, the vast majority of virus strain in the current study period (from April 2021 to September 2021) was assumed to be delta variant, and the current results could be applied to COVID-19 with the delta variant.The generalizability of the current study for the COVID-19 with other variants should be carried out carefully.Finally, the demographics and practice patterns as well as the clinical outcomes in Japan may differ from those outside Japan.Thus, it should be interpreted with caution whether the current results could be extrapolated to patients in different regions and countries.

Conclusions
Among hospitalized patients with clinically stable COVID-19 at admission, patients who did not worsen in COVID-19 severity after admission rarely developed thrombosis, although patients with worsening of COVID-19 severity after admission more often received prophylactic anticoagulation and might have a potential higher risk of thrombosis.