The use of direct oral anticoagulants after pulmonary embolism regarding the bleeding risk in the countries without reimbursement Results from the Regional Pulmonary Embolism Registry

The use of direct oral anticoagulants after pulmonary embolism regarding the bleeding risk in the countries without reimbursement Results from the Regional Pulmonary Embolism Registry | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 28 September 2025 V1 Latest version Share on The use of direct oral anticoagulants after pulmonary embolism regarding the bleeding risk in the countries without reimbursement Results from the Regional Pulmonary Embolism Registry Authors : Sandra Pekovic [email protected] , Darko Tasić , Marija Benić , Boris Dzudović , Sonja Šalinger 0000-0001-9657-1665 , Jeftić , Vladimir Miloradović , … Show All … , Tamara Preradović Kovačević , Bjanka Bozović , Irena Mitevska , Bojan Mitrović , Aleksandar Nešković , and Slobodan Obradović Show Fewer Authors Info & Affiliations https://doi.org/10.22541/au.175906449.97413669/v1 240 views 107 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background: Direct oral anticoagulants (DOACs) have become the standard of care for the treatment of pulmonary embolism (PE), but optimal drug selection requires individualized assessment, particularly in health systems without reimbursement policies. Objectives: To identify the clinical characteristics of patients treated with direct oral anticoagulants (DOACs) for pulmonary embolism and to compare the risk, frequency, and types of bleeding events associated with the use of different DOACs. Methods: This retrospective cohort study analysed 969 patients from the Regional Pulmonary Embolism Registry (REPER) who were discharged with DOAC therapy between January 2015 and January 2023. Patients were stratified into three groups based on the prescribed DOAC: rivaroxaban, apixaban, or dabigatran. Clinical characteristics, bleeding risk scores (VTE-BLEED and HAS-BLED), and the incidence of major bleeding (MB) events within 90 days were compared. Results: Rivaroxaban was the most frequently prescribed DOAC, followed by apixaban and dabigatran. Patient characteristics significantly influenced drug selection, with apixaban being more commonly used in elderly patients, those with renal impairment, malignancy, or prior bleeding history. Patients with VTE-BLEED score 2 or higher were more often treated with apixaban despite the highest price of this drug. Despite difference in risk profiles for bleeding regarding DOAC use, no statistically significant difference was found in the incidence of MB across the groups (p=0.652). The VTE-BLEED score outperformed HAS-BLED in predicting bleeding events (AUC ROC analysis). Conclusions: Apixaban appeared to be the preferred agents for patients at increased risk of bleeding or with complex comorbidities, including renal dysfunction and cancer. The VTE-BLEED score was confirmed as a tool for guiding anticoagulant selection in acute PE. A personalized, risk-adapted approach for anticoagulation therapy after PE is achieved in spite of the total lack of reimbursement for majority of patients in our registry. Introduction Venous thromboembolism (VTE), encompassing pulmonary embolism (PE) and/or deep vein thrombosis (DVT), represents a significant clinical entity. PE is the third most common cardiovascular event after acute myocardial infarction and cerebrovascular accidents and remains a major contributor to morbidity and mortality [1]. The current therapeutic approach to PE is guided by early risk stratification of mortality. High-risk patients require reperfusion therapy, including systemic thrombolysis and/or catheter-directed interventions. In patients classified as intermediate-high risk, low-molecular-weight heparin (LMWH) and/or continuous unfractionated heparin (UFH) are recommended in conjunction with close clinical monitoring. For intermediate-low- and low-risk patients, initial treatment with direct oral anticoagulants (DOACs) is advised [2]. DOACs have been available in Serbia since 2013–2014, and all four agents rivaroxaban, apixaban, edoxaban, and dabigatran—have been evaluated in large, randomized controlled trials published in the New England Journal of Medicine [3-6]. For more than six decades, vitamin K antagonists (VKAs) were the standard of care for oral anticoagulation. Although effective, VKAs are associated with numerous limitations that have largely been addressed by DOACs. These agents act by inhibiting a single coagulation factor: thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, edoxaban). Compared to VKAs, DOACs offer several clinical advantages, including predictable pharmacokinetics and pharmacodynamics, fixed dosing, fewer drug and food interactions, and a lower risk of major bleeding, all without the need for routine laboratory monitoring [7]. DOACs are characterized by a rapid onset of action (within hours), a half-life of approximately 10 hours, and complete absorption within 24 hours [8]. Their metabolism involves P-glycoprotein transport and the cytochrome P450 (CYP3A4) enzyme system [8]. Owing to their renal and hepatic clearance, DOACs are contraindicated in patients with creatinine clearance (CrCl) <15 mL/min and those with significant hepatic impairment. Additionally, due to placental transfer, their use is not recommended during pregnancy and lactation. According to the 2019 ESC guidelines, DOACs are contraindicated in patients with severe renal dysfunction, antiphospholipid syndrome, or in pregnant individuals [2]. While DOACs represent an effective and convenient alternative to VKAs, safety remains a paramount concern, particularly with regard to bleeding complications. Zhou et al. demonstrated in a recent meta-analysis that DOACs are associated with a more favorable safety profile, particularly regarding MB and intracranial haemorrhage, compared to VKAs [9]. Nonetheless, bleeding remains the most frequent and clinically significant complication of anticoagulant therapy, underscoring the importance of careful patient selection and close monitoring. Several bleeding risk scores are available in clinical practice, such as HAS-BLED, HEMORR_2HAGES, and ORBIT; however, these tools were primarily developed for patients with atrial fibrillation. Introduced in 2016, the VTE-BLEED score is the first validated tool specifically designed to assess bleeding risk in patients with VTE undergoing long-term anticoagulation. This score incorporates six variables: active cancer, male sex, anaemia, age ≥60 years, prior bleeding, and renal dysfunction. A score of ≥2 indicates an increased risk of major bleeding [10]. Given the expanding use of DOACs in the treatment of VTE, accurate bleeding risk stratification particularly with tools like the VTE-BLEED score has become an essential component of individualized clinical decision-making. Aim: 1. To identify the clinical characteristics of patients treated with direct oral anticoagulants (DOACs) for pulmonary embolism (PE) from the multicenter, multinational PE registry from the western Balkan countries. 2. To compare the risk, frequency, and types of bleeding events associated with the use of different DOACs in this registry. 3. To compare outcomes among different agents. Methods Data for this study were obtained from the Regional Pulmonary Thromboembolism Registry (REPER), which includes information on patients hospitalized and treated in six University Clinical Centers (UCCs) and hospitals across the Republic of Serbia, as well as from one UCC each in Bosnia and Herzegovina, North Macedonia, and Montenegro. The diagnosis of acute pulmonary thromboembolism (PTE) was confirmed by computed tomography pulmonary angiography (CTPA). All patients included in the study were free from terminal-stage comorbid chronic diseases. Between January 2015 and January 2023, a total of 1,939 patients with confirmed PTE were enrolled in the REPER registry. Of these, 208 patients died during hospitalization and were excluded from further analysis. Among the 1,731 patients discharged for outpatient management, 153 were prescribed low molecular weight heparin (LMWH), 554 vitamin K antagonists (VKA), 975 direct oral anticoagulants (DOACs) and for 49 patients post-discharge treatment data were unavailable. Total of 969 patients who were discharged with DOAC therapy were included in the final analysis. Follow-up outpatient evaluations were conducted one month and three months after hospital discharge. In addition to clinical indications, the decision to initiate DOAC therapy was influenced by the fact that, in Serbia, North Macedonia, and Bosnia and Herzegovina, patients are required to pay the full cost of treatment out-of-pocket—posing a significant financial burden for most of the population in these countries. The patients included in the analysis were categorized into three groups according to the specific DOAC prescribed for continued treatment of PE: Apixaban (Group A), Rivaroxaban (Group R), and Dabigatran (Group D). Edoxaban was not included in the analysis, as it had not been registered in the participating countries by January 2023. The following clinical and demographic characteristics were compared among the three groups: age, sex, body mass index (BMI), recent surgery (within 3 weeks to 6 months), renal function (creatinine clearance, CrCl), history of bleeding within one year prior to the acute PE episode, use of medications associated with increased bleeding risk (nonsteroidal anti-inflammatory drugs [NSAIDs], corticosteroids, and antiplatelet agents), and comorbidities. Among comorbid conditions, we specifically assessed those with a known impact on bleeding risk, including chronic heart failure, chronic obstructive pulmonary disease (COPD), arterial hypertension, coronary artery disease, diabetes mellitus, active malignancy (defined as diagnosis or treatment within the past 6 months, presence of metastatic disease, or recurrence within 5 years), anaemia (haemoglobin <100 g/L), and chronic liver disease. The analysis included the frequency and types of bleeding events observed in each group, as well as comparative assessment between groups. In addition, VTE-BLEED and HAS-BLED scores were calculated and compared across all three DOAC groups. Statistical Analysis Descriptive statistics were used to summarize the data. Continuous variables were expressed as means with standard deviation, medians, standard deviations with 25-75 percentiles interval or frequences depending on whether variables are continuous or categorical and the normality of distribution, while categorical variables were presented as absolute numbers and percentages. Since the distribution of continuous variables did not meet the assumptions of normality, non-parametric tests were employed. Specifically, the Kruskal-Wallis test and the Bonferroni correction for p values of multiply testing was used to compare bleeding risk scores (VTE-BLEED and HAS-BLED) among treatment groups. Differences in categorical variables were assessed using the Chi-square test. To evaluate the ability of bleeding risk scores to predict major bleeding within 90 days of DOAC initiation, receiver operating characteristic (ROC) curve analysis was performed. Time-to-event data were analysed using Kaplan–Meier survival curves, and differences between groups were tested with the Log Rank test. A p-value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS statistical software. Results A total of 969 patients diagnosed with acute pulmonary embolism (PE) who were discharged on direct oral anticoagulants (DOACs) were included in the analysis. Patients were stratified into three treatment groups based on the prescribed DOAC: rivaroxaban (R group, n = 512), dabigatran (D group, n = 168), and apixaban (A group, n = 289). The mean age of the entire cohort was 64.9 ± 14.5 years, with females comprising 47.2% of the population. The most common comorbidities were arterial hypertension (60,1%), anaemia (23,53%) and diabetes mellitus (17,65%). Recent surgery was reported in 17,34% of the patients included in the study. Most patients had intermediate-risk PE (54,39%), while low risk was identified in 35,71%, and high risk in 9.9%. The distribution of PE severity varied between the DOAC groups: apixaban was more frequently prescribed in patients with high risk (30,21% of patient with high risk PE), whereas rivaroxaban was the most common choice among those with low-risk PE (54,05%) ( p < 0.058). All patients received initial anticoagulation with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) for variable durations, followed by initiation of direct oral anticoagulant (DOAC) therapy. It should be noted that data were collected across multiple health centers in different countries, which may account for minor numerical inconsistencies in some variables. A higher proportion of patients receiving chronic therapy with medications that increase the risk of bleeding were treated with rivaroxaban (42.02%) and apixaban (39.29%). A statistically significant difference was confirmed in the distribution of these patients among the study groups (p<0.001). Among the patients treated for acute PE, 92 had an active malignancy at the time of diagnosis. Of these, 39 (13.49% of the apixaban group), 43 (8.4% of the rivaroxaban group), and 10 (5.95% of the dabigatran group) received the corresponding DOAC. The distribution differed significantly between groups (p=0.015). A complete overview of baseline characteristics of patients and comorbidities is presented in Table 1. Age Distribution Older patients (≥60 years) were the majority in all three treatment groups, with the highest proportion in the A group. Patients older than 75 years comprised 20.7% of the total cohort, with the highest proportions in the A and R groups (43.8% and 42.8%, respectively), and the lowest in the D group (13.4%). These results are presented in Table 1 and Table 2. Renal function assessment revealed that 236 patients (24.4%) had impaired kidney function (CrCl <60 mL/min), including 32 patients (3.3%) with severe impairment (CrCl <30 mL/min). The distribution of renal insufficiency by treatment group is shown in Table 2. Body Mass and BMI Body weight and height data were available for 779 patients. BMI distribution was relatively even, with overweight status being the most common. Bleeding as an adverse event Despite differences in the type, frequency, and severity of risk factors for bleeding as a complication of DOAC therapy, there was no statistically significant difference in the incidence of major bleeding within 90 days of therapy initiation among the R, D, and A groups (2.9% vs. 3.1% vs. 1.8%, respectively; Log Rank p=0.652). These findings are shown in Figure 1. A closer look at Figure 1 reveals that in the dabigatran group, all major bleeding events occurred within the first 20 days of therapy, unlike the apixaban group (up to day 65) and rivaroxaban group (throughout the full 90-day follow-up period). Bleeding Risk Assessment among patients included in study To assess bleeding risk, two scoring systems were used: VTE-BLEED and HAS-BLED. Although the median scores for both systems were the same across all DOAC groups (VTE-BLEED = 1.5; HAS-BLED = 1.0), the distribution of values within each group varied substantially. Significant differences in the distribution of risk score values were confirmed by the Kruskal-Wallis test. Patients in group A (Apixaban) had the highest average rank for the VTE-BLEED score compared to patients in groups R (Rivaroxaban) and D (Dabigatran) (531.02 vs. 464.36 vs. 464.93, respectively; p = 0.003). The same trend was observed for the HAS-BLED score (544.11 vs. 461.28 vs. 466.25, respectively; p < 0.001). These findings are shown in Figures 1 and 2. Receiver Operating Characteristic (ROC) curve analysis demonstrated that the VTE-BLEED score was significantly superior to the HAS-BLED score in predicting the risk of major bleeding complications during the first 90 days of DOAC treatment which is shown in Figure 3. There was a statistically significant difference in the incidence of major bleeding between patients with VTE-BLEED scores ≤2 and those with scores >2 (Log Rank p = 0.008), with higher bleeding rates observed among patients with scores above 2. This is shown in Figure 2. Among all evaluated patients, the VTE-BLEED score could be determined in 960 cases. Of these, 423 patients (44.0%) had a VTE-BLEED score ≥2. Their distribution across treatment groups was as follows: group R – 209 patients (49.4%), group D – 67 patients (15.8%), and group A – 147 patients (34.8%) which is shown in Table 2. When analysing each treatment group individually, patients with increased bleeding risk (VTE-BLEED ≥2) comprised half of the Apixaban group, while their proportion was lower in the Rivaroxaban (41.3%) and Dabigatran (40.6%) groups. These data are presented in Table 2. Chi-square testing confirmed a statistically significant difference in the proportion of patients with VTE-BLEED ≥2 among the treatment groups (p < 0.05). Discussion This study, based on data from the REPER registry, provides insight into the current patterns of DOAC prescription in patients with acute pulmonary embolism (PE) in real-world clinical practice. In the observed patient population, three DOACs apixaban, rivaroxaban, and dabigatran were used for the treatment of acute pulmonary embolism (PE), but their distribution among patients was not uniform. Rivaroxaban was the most prescribed agent while dabigatran was used least frequently. The choice of a particular DOAC was influenced not only by their pharmacokinetic and pharmacodynamic properties but also by their availability and cost. Although all three DOACs were available on the market during the observation period starting from January 2015, they entered the Serbian market at different times: dabigatran in 2012, rivaroxaban in September 2013, and apixaban in June 2014. Additionally, in Serbia, Bosnia and Herzegovina, and North Macedonia, the cost of DOAC therapy was not reimbursed by national health insurance systems during the study period, and the financial burden was borne entirely by the patients and their families. Rivaroxaban was significantly less expensive than the other two DOACs, which likely contributed to its widespread use in this patient population. Other factors that favoured its more frequent use included once-daily dosing, which supports better patient adherence, and its indication for both initial and long-term treatment of PE. Older (≥60 years) and very elderly patients (≥75 years) made up the majority of the study population, reflecting the well-established association between advancing age and increased risk of thromboembolic events. [11]. Advanced age is also associated with a higher burden of comorbidities, an increased risk of recurrent thromboembolic events, and a greater likelihood of bleeding complications [12]. It is well known that DOACs are more effective than VKAs in preventing recurrent PE in the elderly [12]. All the above explains the high proportion of old people in the observed cohort. Among patients aged ˃75 years, the majority were treated with either apixaban or rivaroxaban, whereas only a minority received dabigatran. Analysis of the age distribution across treatment groups revealed that the apixaban group had the highest proportion of very elderly patients, in contrast to the rivaroxaban group. The difference in the distribution of patients aged ˃75 years among the three treatment groups was statistically significant (p < 0.001), indicating a preferential use of apixaban in this vulnerable population. These observations indicate a clear preference for apixaban in the management of very elderly patients, whereas dabigatran was used considerably less often in this subgroup. This prescribing pattern is likely influenced by evidence demonstrating that advanced age does not significantly alter the pharmacokinetics or pharmacodynamics of apixaban in a manner that would necessitate dose adjustment [13]. Comparable data exist for rivaroxaban, but only at doses up to 10 mg, which are lower than those typically employed in the treatment of pulmonary embolism [14,15]. In contrast, clinical guidelines recognize advanced age as a factor that may require dose reduction for dabigatran, although a reduced dose is not recommended for the treatment of venous thromboembolism [16]. Furthermore, based on the clinical experience of the authors, dabigatran appears to be associated with a higher risk of bleeding in elderly patients, which may have further contributed to its limited use in this population. Regarding sex distribution, no significant differences were observed in favour of either sex, both in the overall study population and within individual DOAC groups. Therefore, sex appears to be a clinically insignificant factor in the decision-making process for anticoagulant selection. The majority of patients presented with low or intermediate risk pulmonary thromboembolism (PE), while high-risk cases were relatively infrequent. Rivaroxaban was most commonly used in patients with intermediate and high risk PTE, followed by apixaban, indicating a preference for these two agents in more severe clinical presentations. In contrast, patients treated with dabigatran were predominantly from the low risk category. The preferential use of rivaroxaban and apixaban in patients with intermediate and high risk pulmonary thromboembolism (PE) may be largely attributed to their favourable pharmacokinetic and pharmacodynamic profiles. These agents allow for safe administration in elderly individuals and those with moderate to severe renal impairment without requiring dose adjustment—advantages not shared by dabigatran. Moreover, retrospective data support the efficacy and safety of rivaroxaban and apixaban in this clinical context, particularly following uncomplicated thrombolytic therapy, demonstrating reduced hospital length of stay compared to traditional anticoagulants such as warfarin or enoxaparin, with no increase in adverse clinical outcomes [17]. In addition to clinical considerations, the predominant use of rivaroxaban—particularly among patients with intermediate and high-risk PE may also be influenced by practical advantages, including lower cost and once daily dosing, both of which contribute to improved patient adherence. Apixaban, although administered twice daily, was also frequently used in these subgroups, likely due to its well-established safety profile in older and more comorbid populations. Renal function emerged as an important factor influencing the choice of anticoagulant therapy. Among patients with impaired renal function (creatinine clearance <60 mL/min), the highest absolute number was observed in the rivaroxaban group, which reflects its predominance in the overall study population. However, when examining the proportion of patients with renal impairment within each treatment group, apixaban was more frequently prescribed in this subgroup relative to the group size, suggesting a preferential use of this agent in patients with moderate to severe renal dysfunction A statistically significant difference in renal function distribution was observed among the treatment groups (p<0.05). These findings indicate that apixaban was more commonly selected for patients with renal impairment, despite being the most recently introduced DOAC in the REPER registry countries. In contrast, dabigatran was infrequently used in this subgroup, consistent with current recommendations discouraging its use in patients with severe renal dysfunction (creatinine clearance <30 mL/min), a limitation not shared by rivaroxaban and apixaban. Previous studies in patients with atrial fibrillation have demonstrated a lower incidence of bleeding with apixaban compared to rivaroxaban and warfarin [18]. Emerging evidence suggests that this safety advantage may extend to patients with pulmonary embolism [19]., potentially contributing to the observed prescribing preference for apixaban in patients with renal insufficiency in this cohort. Among patients with a history of prior bleeding, apixaban emerged as the most frequently prescribed direct oral anticoagulant (DOAC). This prescribing pattern likely reflects its favourable pharmacokinetic and pharmacodynamic characteristics, a well-established safety profile supported by clinical evidence. Furthermore, the distribution of these patients across treatment groups differed significantly (p = 0.025), underscoring the influence of prior bleeding history on anticoagulant selection. In patients with active malignancy, both apixaban and rivaroxaban were commonly prescribed, with a modest preference observed for apixaban. A statistically significant difference was observed in the distribution of patients with active cancer across treatment groups, with apixaban demonstrating the highest relative representation (p=0.015). This prescribing pattern may be influenced by a more extensive body of evidence supporting the safety of apixaban in oncology populations, particularly in terms of bleeding risk [20]. Despite differences in the type, frequency, and severity of bleeding risk factors among the treatment groups, no statistically significant difference was observed in the incidence of major bleeding within 90 days of initiating DOAC therapy between the rivaroxaban, dabigatran, and apixaban groups. These findings suggest that the choice of DOAC in the treatment of patients with acute PTE was based on a comprehensive understanding of the pharmacokinetic and pharmacodynamic profiles of individual agents, aligned with patient-specific clinical characteristics and bleeding risk. To evaluate bleeding risk, the VTE-BLEED and HAS-BLED scoring systems were employed. ROC curve analysis demonstrated superior predictive performance of the VTE-BLEED score over HAS-BLED for identifying patients at increased risk of major bleeding within the first 90 days of DOAC therapy. This suggests that VTE-BLEED may be better suited for clinical decision-making regarding anticoagulant selection in patients with acute pulmonary embolism. A statistically significant difference in the incidence of major bleeding was observed between patients with VTE-BLEED scores ≤2 and those with scores >2, with a higher bleeding risk associated with elevated scores. Accordingly, a VTE-BLEED score ≥2 should be considered indicative of high bleeding risk in the context of DOAC therapy for PTE. Significant differences were also observed in the distribution of bleeding risk scores among treatment groups. Patients treated with apixaban demonstrated the highest mean VTE-BLEED ranks compared to those receiving rivaroxaban or dabigatran. Among individuals classified as high risk for bleeding (VTE-BLEED ≥2), apixaban and rivaroxaban were the most commonly prescribed DOACs, whereas dabigatran was used less frequently. A statistically significant difference in the distribution of high-risk patients across treatment groups was confirmed using the χ² test (p < 0.05). These findings suggest a preferential use of apixaban in patients with elevated bleeding risk, with rivaroxaban representing a commonly used alternative. These findings highlight the importance of individual risk stratification in the selection of DOAC therapy for PE. In clinical practice, patient characteristics such as age, renal function, history of bleeding, and presence of malignancy appear to influence the choice of DOAC, with a notable tendency toward prescribing apixaban in higher-risk patients. Limitations of our study include its retrospective design and reliance on registry data, which may be subject of incomplete clinical information. Despite these limitations, the study provides relevant real-world data on DOAC use in PE and emphasizes the clinical utility of the VTE-BLEED score in early bleeding risk assessment. Conclusion This study highlights that clinical factors such as advanced age, renal dysfunction, active malignancy, prior bleeding, and concomitant use of high-risk medications significantly influence the choice of DOAC in patients with acute pulmonary embolism. Apixaban and rivaroxaban were most commonly prescribed, with apixaban showing a favourable safety profile in high-risk populations. The VTE-BLEED score outperformed HAS-BLED in predicting early bleeding events, with a threshold ≥2 identifying patients at increased risk. These findings support the use of a personalized, risk-adapted approach to DOAC selection in PE management, particularly in resource-limited settings. Prospective studies are needed to confirm these real-world observations and guide clinical decision-making. References 1. Farid-Zahran M, Méndez-Bailón M, Pedrajas JM, Alonso-Beato R, Galeano-Valle F, Sendín Martín V, et al. Prognostic significance of heart failure in acute pulmonary embolism: a comprehensive assessment of 30-day outcomes. J Clin Med. 2024;13(5):1284. doi:10.3390/jcm13051284 2. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020;41(4):543–603. 3. EINSTEIN–PE Investigators. 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Mani H, Lindhoff-Last E. New oral anticoagulants in patients with nonvalvular atrial fibrillation: a review. Drug Des Devel Ther. 2014;8:789–98. doi:10.2147/DDDT.S41644 9. Cao Y, Zheng Y, Li S, Liu F, Xue Z, Yin K, et al. An updated meta-analysis of DOACs vs. VKAs in atrial fibrillation patients with bioprosthetic heart valve. Front Cardiovasc Med. 2022;9:898118. doi:10.3389/fcvm.2022.898118 10. Klok FA, Barco S, Konstantinides SV. External validation of the VTE-BLEED score. Thromb Haemost. 2016;116(3):423–9. doi:10.1160/TH16-10-0810 11. Mithoowani S, Bungard T, et al. Multidisciplinary expert guidance for the management of severe bleeding in oral anticoagulation. TH Open. 2024; [Epub ahead of print]. doi:10.1055/a-2464-2887 12. Tritschler T, Castellucci LA, Van Es N, Aujesky D, Le Gal G. Treatment of venous thromboembolism in elderly patients in the era of direct oral anticoagulants. Pol Arch Intern Med. 2020;130(3):221–8. 13. Frost CE, Song Y, Shenker A, Wang J, Barrett YC, Schuster A, et al. Effects of age and sex on apixaban pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2015;54(6):651–62. doi:10.1007/s40262-014-0228-0 14. Hou H, Li A, Zhang L, Qin X, Jiang Y, Zhao H. Effectiveness, safety, and bleeding related to rivaroxaban in elderly patients. Clin Appl Thromb Hemost. 2020;26:1076029620925923. doi:10.1177/1076029620925923 15. Kubitza D, Becka M, Roth A, Mueck W. Influence of age and gender on rivaroxaban pharmacokinetics. J Clin Pharmacol. 2013;53(3):249–55. doi:10.1002/jcph.5 16. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–52. doi:10.1056/NEJMoa0906598 17. Wolfe A, Phillips A, Tierney DM, Melamed R, Qadri G, Lillyblad M, et al. DOAC initiation timing and outcomes after thrombolysis in PE. Clin Appl Thromb Hemost. 2023;29:10760296231156414. doi:10.1177/10760296231156414 18. Fu EL, Desai RJ, Paik JM, Kim DH, Zhang Y, Mastrorilli JM, et al. Comparative safety and effectiveness of warfarin or rivaroxaban vs. apixaban in patients with advanced CKD. Am J Kidney Dis. 2024;83(3):293–305.e1. doi:10.1053/j.ajkd.2023.08.017 19. Dawwas GK, Brown J, Dietrich E, Park H. Effectiveness and safety of apixaban vs. rivaroxaban in VTE. Lancet Haematol. 2019;6(1):e20–8. doi:10.1016/S2352-3026(18)30191-1 20. Giustozzi M, Agnelli G, Del Toro-Cervera J, Klok FA, Rosovsky RP, Martin AC, et al. DOACs for treatment of VTE associated with cancer: a meta-analysis. Thromb Haemost. 2020;120(7):1128–36. doi:10.1055/s-0040-1712098 Conflict of interest: The authors declare no conflict of interest. Funding: This research recived no specific grant from any funding agency in the public, commercial, or not-for-profit sectors . Supplement Table 1. Baseline characteristics of the study group with respect of the kind of DOAC used. Age, Mean, y±SD 61±16 61±15 66±16 <0.001 ≥60 y, n (%) 316 (61.72) 107 (62.69) 201 (69.55) 0.025 Females, n (%) 253 (49.41) 82 (48.81) 166 (57.44) 0.082 CHF, n (%) EFLV<40% 18 (3.52) 5 (2.98) 8 (2.77) 0.927 EFLV 40-49% 17 (3.32) 7 (4.17) 8 (2.77) CRF (GFR<60 ml/min), n (%) 110 (21.48) 44 (26.19) 91 (48.15) 0.009 COPD, n (%) 32 (6.25) 13 (7.74) 38 (13.15) 0.004 Arterial hypertension, n (%) 302 (58.98) 103 (61.31) 186 (64.36) 0.420 Coronary disease, n (%) 54 (10.55) 17 (10.12) 17 (5.88) 0.072 Stroke, n (%) 21 (4.10) 9 (5.36) 20 (6.92) 0.230 Diabetes mellitus type 2, n (%) 89 (17.38) 23 (13.69) 59 (20.41) 0.196 Previous bleeding, n (%) 17 (3.32) 12 (7.14) 21 (7.27) 0.025 Chronic use of drugs, n (%) 108 (21.1) 48 (28.57) 101 (34.95) <0.001 Recent surgery, n (%) 74 (14.45) 29 (17.26) 65 (22.49) 0.019 Active malignant disease, n (%) 43 (8.4) 10 (5.95) 39 (13.49) 0.015 Anaemia, n (%) 114 (22.26) 38 (22.62) 76 (26.30) 0.460 Chronic liver lesion, n (%) 18 (3.52) 6 (3.57) 12 (4.15) 0.904 PE severity, n (%) Low risk 187 (36.52) 67 (39.88) 92 (31.83) 0.058 Intermediate risk 264 (51.56) 95 (56.55) 168 (58.13) High risk 61 (11.91) 6 (3.57) 29 (10.03) Table 2. Use of different DOAC according to some important risk factors for bleeding. Age > 75 y Renal function CrCl > 60 ml/min CrCl 30-59 ml/min CrCl < 30 ml/min VTE-BLED score ≥ 2 86 (16.8) 402 (78.8) 91 (17.8) 17 (3.3) 209 (41.3) 27 (16.1) 127 (75.6) 38 (22.6) 3 (1.8) 67 (40.6) 88 (30.4) 201 (69.8) 75 (26.0) 12 (4.2) 147 (50.9) <0.001 0.043 0.020 Figure 1. Kaplan-Meier curves for major bleeding regarding the DOAC use. Log Rank p=0.652 Figure 2. Kaplan-Meier curves for major bleeding by VTE-BLEED score cut-off (2 or less vs. greater than 2), Log Rank p = 0.008 Figure 3. ROC curves for VTE-BLEED and HAS-BLED scores in predicting major bleeding within 90 days for all three types of DOACs Information & Authors Information Version history V1 Version 1 28 September 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords bleeding risk direct oral anticoagulants pulmonary embolism vte-bleed score Authors Affiliations Sandra Pekovic [email protected] Institute for Pulmonary Diseases of Vojvodina View all articles by this author Darko Tasić Institute for Pulmonary Diseases of Vojvodina View all articles by this author Marija Benić Institute for Pulmonary Diseases of Vojvodina View all articles by this author Boris Dzudović Vojnomedicinska akademija View all articles by this author Sonja Šalinger 0000-0001-9657-1665 Universitetski klinicki centar u Nisu View all articles by this author Jeftić Klinicki centar Kragujevac View all articles by this author Vladimir Miloradović Klinicki centar Kragujevac View all articles by this author Tamara Preradović Kovačević University of Banja Luka View all articles by this author Bjanka Bozović Klinicki Centar Crne Gore View all articles by this author Irena Mitevska University Clinic of Cardiology View all articles by this author Bojan Mitrović University of Belgrade View all articles by this author Aleksandar Nešković University of Belgrade View all articles by this author Slobodan Obradović Vojnomedicinska akademija View all articles by this author Metrics & Citations Metrics Article Usage 240 views 107 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Sandra Pekovic, Darko Tasić, Marija Benić, et al. 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