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Ann Phlebology 2024; 22(2): 39-43

Published online December 31, 2024

https://doi.org/10.37923/phle.2024.22.2.39

© Annals of phlebology

Direct Oral Anticoagulants in Fragile Patients with Venous Thromboembolism

Hojong Park, M.D., Ph.D.1, Sang Jun Park, M.D., Ph.D.1, Jeong-Ik Park, M.D., Ph.D.1, Jin Sung Kim, M.D.1, Jin Ah Kwon, M.D.1, Hyangkyoung Kim, M.D., Ph.D2

Author Affiliations
1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 2Department of Surgery, Ewha Womans University Medical Center, Ewha Womans University College of Medicine, Seoul, Korea

Correspondence to : Hyangkyoung Kim
Department of Surgery, Ewha Womans University Medical Center, Ewha Womans University College of Medicine
Tel: 82-2-2650-5587
Fax: 82-2-2650-5273
E-mail: hkkim77@ewha.ac.kr

Received: June 26, 2024; Revised: November 6, 2024; Accepted: November 7, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Venous thromboembolism (VTE), a severe condition comprising deep vein thrombosis and pulmonary embolism, requires prompt treatment. Traditional therapies include heparin, low-molecular-weight heparin, and warfarin. Direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban has revolutionized VTE management. Clinical trials show that DOACs are as effective as traditional anticoagulants in preventing recurrent VTE, with similar or lower rates of major bleeding. However, DOAC use is complex in vulnerable populations—those with comorbidities, chronic kidney disease, cancer, and advanced age—due to higher VTE and bleeding risks from polypharmacy and altered pharmacokinetics. Trials have shown promising results for DOACs, but these studies often include few patients from these high-risk groups. Moreover, while DOACs are validated for atrial fibrillation, these findings may not apply directly to patients with VTE due to different dosing. In this study, we aimed to address this gap by reviewing the literature on the efficacy and safety of DOACs in these vulnerable populations.

Keywords Venous thromboembolism, Direct oral anticoagulants, Fragile patients, Bleeding, Recurrence

Introduction

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Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), which poses serious and potentially life-threatening risks that necessitate prompt medical intervention. The conventional treatments for VTE include traditional anticoagulants such as heparin, low-molecular-weight heparin (LMWH), and warfarin. However, the advent of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban has significantly transformed VTE management. Clinical trials consistently show that DOACs are as effective as traditional anticoagulants in preventing recurrent VTE, with comparable or lower incidences of major bleeding.

Patients with multiple comorbidities, particularly those with cancer or advanced age, are at an elevated risk for VTE [1,2]. For these individuals, polypharmacy and altered pharmacokinetics can increase the likelihood of major bleeding, thus making anticoagulant use particularly complex [3,4]. Despite the promising results from randomized controlled trials on DOAC use, only a small fraction of patients with multiple comorbidities have been included in these investigations [5]. Numerous studies have validated the efficacy and safety of DOACs in patients with atrial fibrillation; however, these findings may not be directly applicable to patients with VTE due to differences in dosage regimen [6]. Consequently, in this study, we aimed to assess the efficacy and safety of DOACs in vulnerable populations in real-world settings, specifically focusing on patients with chronic kidney disease, cancer, and advanced age.

DOACs in patients with cancer-associated thrombosis (DOACs versus other anticoagulants)

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Patients with cancer are at an increased risk of VTE; this risk is fourfold to sevenfold higher than in patients without cancer [7]. Mortality is also three times higher in patients with cancer and VTE compared with those without VTE [8,9]. As cancer survival rates increase, the incidence of cancer-associated thrombosis is expected to rise, highlighting the importance of effective VTE prevention and treatment in these patients [10].

Traditionally, LMWH has been the treatment of choice for VTE in patients with cancer. However, early clinical trials investigating DOACs prompted further studies into their use in this population [11,12]. DOACs have shown similar efficacy and safety to warfarin for treating cancer-associated VTE, leading to comparisons with LMWH [13]. Major trials such as HOKUSAI VTE Cancer, SELECT-D, ADAM VTE, and Caravaggio found that DOACs significantly reduced recurrent VTE risk. However, bleeding risks varied across studies, necessitating careful consideration of DOAC safety [14]. Meta-analyses of randomized controlled trials (RCTs) also supported the use of DOACs, indicating a reduced risk of recurrent VTE without a significant increase in major bleeding compared with dalteparin [15]. Real-world analyses further confirmed that rivaroxaban, for example, had a lower recurrence risk compared to vitamin K antagonists (VKA) or LMWH, with similar bleeding risks [16]. The CANVAS trial echoed these findings, showing DOACs to be non-inferior to LMWH in preventing recurrent VTE and not significantly different regarding major bleeding or death [17]. International guidelines now recognize DOACs as acceptable alternatives for cancer-associated VTE, especially in selected patients. However, caution is advised for patients with gastrointestinal or genitourinary malignancies due to bleeding risks [18,19]. The CASINI trial also highlighted rivaroxaban’s safety and efficacy of rivaroxaban for thromboprophylaxis in patients with cancer [20]. A systematic review and meta-analysis discovered that DOACs significantly reduced VTE recurrence without increasing bleeding risk compared with traditional anticoagulants like VKA, LMWH, and dalteparin [21].

DOACs have several advantages over warfarin, including a shorter onset time and half-life, as well as fewer drug interactions, making them preferable. In cancer patients, maintaining appropriate warfarin dosages is often challenging due to cancer related treatments like chemotherapy, biopsy, or surgery [22].

In elderly patients with cancer (aged ≥75 years) and VTE, the rate of recurrent VTE requiring hospitalization was lower in the DOAC group compared to the warfarin group [23]. Moreover, aggregated studies have reported that DOACs are cost-effective compared with LMWH in treating cancer-associated thrombosis [14].

DOAC in patients with chronic kidney disease (stage 2)

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The effectiveness and safety of direct oral anticoagulants (DOACs) in patients with chronic kidney disease (CKD) is a subject of significant interest. Notably, four RCTs have compared DOACs with warfarin for treating VTE in patients with CKD having a creatinine clearance (CrCl) of 30–50 ml/min. The findings show no difference in efficacy and either similar or lower rates of major bleeding, particularly with apixaban and rivaroxaban [24-27]. However, there are limited studies on patients with CrCl <30 ml/min due to their exclusion from many DOAC trials, primarily because of the increased bleeding risk associated with uremia-induced platelet dysfunction and the renal elimination of DOACs, which can lead to drug accumulation and higher bleeding risk [28].

A systematic review and meta-analysis involving 11 VTE-related studies found that among CKD patients receiving treatment for acute DVT, recurrent VTE or VTE-related death was lower in the DOAC group compared to the placebo. The results were inconclusive when compared with VKAs. DOACs appeared to be an effective treatment option for VTE in patients with CKD, but further data are needed. This study compiled trials involving patients with VTE and concomitant CKD and atrial fibrillation (AF), dialysis access, and other cardiovascular diseases. Compared with VKAs, DOACs did differ significantly; however, they reduced the risk of major bleeding [29]. In another study involving six RCTs and 19 observational studies, DOACs reduced the risk of stroke, systemic embolism, and VTE by 22% compared with VKA in patients with CKD, and the risk of major bleeding was also reduced by 17%. In patients with stage 4 and 5 CKD, the efficacy and safety of DOACs were similar to VKA, and overall, DOACs were reported to be more effective and safer than VKA, with apixaban showing particularly prominent advantages [30]. There are several systematic reviews comparing DOACs and warfarin in patients with VTE with concomitant CKD. Considering different CrCl levels, these studies reported that DOACs and warfarin showed similar efficacy in preventing recurrent VTE or VTE-related death. However, DOACs were associated with lower bleeding risk, and its efficacy and safety did not statistically differ across different CrCl levels [31-33].

DOACs in patients with advanced chronic kidney disease (stage 4, 5)

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The use of DOACs for patients with advanced CKD has been reported. In a population-based cohort study comparing DOACs and warfarin in patients aged ≥66 years diagnosed with acute VTE concomitant with CKD, no difference in major bleeding was observed between the two groups. Furthermore, there was no difference in major bleeding between DOACs and warfarin across different CKD stages [34]. In a retrospective study utilizing real-world data from a US insurance claims database, 29,790 patients with VTE and CKD were selected, and the results compared the use of apixaban and warfarin. The findings showed that recurrent VTE and major bleeding were associated with lower risk in the apixaban group, and no difference was observed across CKD stages [35]. In a retrospective cohort study, when comparing the use of apixaban and warfarin in patients with advanced CKD (stage 4, 5) who had AF or VTE, it was reported that the risk of major bleeding was significantly lower in the apixaban group after 3 months of treatment. No difference was observed between the two groups regarding stroke and thromboembolism occurrence [28]. Herndon et al. compared warfarin and apixaban in patients with advanced CKD, reporting no difference in major bleeding between both groups, as well as no difference in the occurrence of stroke and VTE [36]. A systematic review of 11 studies evaluating the efficacy and safety of apixaban and warfarin use in patients with advanced CKD discovered that the effects on stroke or systemic embolization and recurrent VTE were similar between the two groups. In addition, it was reported that apixaban had a lower bleeding risk compared with warfarin [37].

Patients with advanced CKD and concurrent VTE pose challenges in treatment decisions, and DOAC use in this population still has limited information available, but apixaban could be considered an option. In one study, when comparing apixaban-based and warfarin-based strategies in patients with VTE and CKD, it was reported that healthcare utilization (hospitalization) was significantly shorter with the apixaban-based strategy. This emphasized the advantages of apixaban [38].

DOACs in patients undergoing dialysis

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In patients undergoing dialysis, there is limited research on anticoagulation for VTE. A retrospective cohort study comparing 2,302 and 9,623 patients on apixaban and warfarin, respectively, while undergoing dialysis found that the apixaban group had a lower risk of bleeding, with similar rates of recurrent VTE and all-cause mortality [39]. Conversely, another study indicated that apixaban might increase bleeding risk in patients undergoing dialysis, due to its high plasma protein binding and minimal removal by hemodialysis, leading to drug accumulation. Due to its high plasma protein binding, apixaban is minimally removed by hemodialysis, leading to its accumulation in the serum of patients undergoing dialysis and potentially resulting in increased trough drug levels. Reports suggest that low-dose apixaban can be effective and minimize bleeding in patients with severe CKD or patients on hemodialysis [40,41].

DOACs in elderly patients

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Elderly patients often exhibit decreased muscle mass, increased body fat, and declines in renal function and stomach pH, which can affect medication clearance and absorption. They are at a higher risk of bleeding compared to the general population, with older women facing a 20–25% higher risk than men. Elderly patients are often underrepresented in clinical trials due to comorbidities, leading to limited evidence on the optimal anticoagulant for this group [24].

Research on DOACs in older populations shows better efficacy and safety than warfarin in treating VTE for patients ≥75 years. Notably, some reviews have reported no difference in bleeding risk between the two [42,43]. A meta-analysis reported similar efficacy between DOACs and warfarin, with the DOAC group showing significantly lower major bleeding risk [44]. Another meta-analysis found DOACs to be more effective than conventional therapy (warfarin, LMWH) in reducing the risk of VTE or VTE-related death, with a lower risk of major bleeding in patients ≥75 years. In a subgroup analysis of the RECOVER trial comparing dabigatran and warfarin, no differences were found in recurrent VTE, VTE-related death, or bleeding risk for patients ≥75 years [24]. However, individual DOACs showed varying outcomes, and many trials had small sample sizes. Further research is needed to establish effective and safe treatments for this demographic [45].

Conclusion

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DOACs are promising for treating VTE in fragile patients with cancer, early stage CKD, and advanced age. However, further research is essential to confirm these benefits, especially in patients with advanced CKD, and caution is needed in patients on dialysis.

REFERENCES

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Review Article

Ann Phlebology 2024; 22(2): 39-43

Published online December 31, 2024 https://doi.org/10.37923/phle.2024.22.2.39

Copyright © Annals of phlebology.

Direct Oral Anticoagulants in Fragile Patients with Venous Thromboembolism

Hojong Park, M.D., Ph.D.1, Sang Jun Park, M.D., Ph.D.1, Jeong-Ik Park, M.D., Ph.D.1, Jin Sung Kim, M.D.1, Jin Ah Kwon, M.D.1, Hyangkyoung Kim, M.D., Ph.D2

1Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, 2Department of Surgery, Ewha Womans University Medical Center, Ewha Womans University College of Medicine, Seoul, Korea

Correspondence to:Hyangkyoung Kim
Department of Surgery, Ewha Womans University Medical Center, Ewha Womans University College of Medicine
Tel: 82-2-2650-5587
Fax: 82-2-2650-5273
E-mail: hkkim77@ewha.ac.kr

Received: June 26, 2024; Revised: November 6, 2024; Accepted: November 7, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Venous thromboembolism (VTE), a severe condition comprising deep vein thrombosis and pulmonary embolism, requires prompt treatment. Traditional therapies include heparin, low-molecular-weight heparin, and warfarin. Direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban has revolutionized VTE management. Clinical trials show that DOACs are as effective as traditional anticoagulants in preventing recurrent VTE, with similar or lower rates of major bleeding. However, DOAC use is complex in vulnerable populations—those with comorbidities, chronic kidney disease, cancer, and advanced age—due to higher VTE and bleeding risks from polypharmacy and altered pharmacokinetics. Trials have shown promising results for DOACs, but these studies often include few patients from these high-risk groups. Moreover, while DOACs are validated for atrial fibrillation, these findings may not apply directly to patients with VTE due to different dosing. In this study, we aimed to address this gap by reviewing the literature on the efficacy and safety of DOACs in these vulnerable populations.

Keywords: Venous thromboembolism, Direct oral anticoagulants, Fragile patients, Bleeding, Recurrence

Introduction

Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), which poses serious and potentially life-threatening risks that necessitate prompt medical intervention. The conventional treatments for VTE include traditional anticoagulants such as heparin, low-molecular-weight heparin (LMWH), and warfarin. However, the advent of direct oral anticoagulants (DOACs) such as dabigatran, rivaroxaban, apixaban, and edoxaban has significantly transformed VTE management. Clinical trials consistently show that DOACs are as effective as traditional anticoagulants in preventing recurrent VTE, with comparable or lower incidences of major bleeding.

Patients with multiple comorbidities, particularly those with cancer or advanced age, are at an elevated risk for VTE [1,2]. For these individuals, polypharmacy and altered pharmacokinetics can increase the likelihood of major bleeding, thus making anticoagulant use particularly complex [3,4]. Despite the promising results from randomized controlled trials on DOAC use, only a small fraction of patients with multiple comorbidities have been included in these investigations [5]. Numerous studies have validated the efficacy and safety of DOACs in patients with atrial fibrillation; however, these findings may not be directly applicable to patients with VTE due to differences in dosage regimen [6]. Consequently, in this study, we aimed to assess the efficacy and safety of DOACs in vulnerable populations in real-world settings, specifically focusing on patients with chronic kidney disease, cancer, and advanced age.

DOACs in patients with cancer-associated thrombosis (DOACs versus other anticoagulants)

Patients with cancer are at an increased risk of VTE; this risk is fourfold to sevenfold higher than in patients without cancer [7]. Mortality is also three times higher in patients with cancer and VTE compared with those without VTE [8,9]. As cancer survival rates increase, the incidence of cancer-associated thrombosis is expected to rise, highlighting the importance of effective VTE prevention and treatment in these patients [10].

Traditionally, LMWH has been the treatment of choice for VTE in patients with cancer. However, early clinical trials investigating DOACs prompted further studies into their use in this population [11,12]. DOACs have shown similar efficacy and safety to warfarin for treating cancer-associated VTE, leading to comparisons with LMWH [13]. Major trials such as HOKUSAI VTE Cancer, SELECT-D, ADAM VTE, and Caravaggio found that DOACs significantly reduced recurrent VTE risk. However, bleeding risks varied across studies, necessitating careful consideration of DOAC safety [14]. Meta-analyses of randomized controlled trials (RCTs) also supported the use of DOACs, indicating a reduced risk of recurrent VTE without a significant increase in major bleeding compared with dalteparin [15]. Real-world analyses further confirmed that rivaroxaban, for example, had a lower recurrence risk compared to vitamin K antagonists (VKA) or LMWH, with similar bleeding risks [16]. The CANVAS trial echoed these findings, showing DOACs to be non-inferior to LMWH in preventing recurrent VTE and not significantly different regarding major bleeding or death [17]. International guidelines now recognize DOACs as acceptable alternatives for cancer-associated VTE, especially in selected patients. However, caution is advised for patients with gastrointestinal or genitourinary malignancies due to bleeding risks [18,19]. The CASINI trial also highlighted rivaroxaban’s safety and efficacy of rivaroxaban for thromboprophylaxis in patients with cancer [20]. A systematic review and meta-analysis discovered that DOACs significantly reduced VTE recurrence without increasing bleeding risk compared with traditional anticoagulants like VKA, LMWH, and dalteparin [21].

DOACs have several advantages over warfarin, including a shorter onset time and half-life, as well as fewer drug interactions, making them preferable. In cancer patients, maintaining appropriate warfarin dosages is often challenging due to cancer related treatments like chemotherapy, biopsy, or surgery [22].

In elderly patients with cancer (aged ≥75 years) and VTE, the rate of recurrent VTE requiring hospitalization was lower in the DOAC group compared to the warfarin group [23]. Moreover, aggregated studies have reported that DOACs are cost-effective compared with LMWH in treating cancer-associated thrombosis [14].

DOAC in patients with chronic kidney disease (stage 2)

The effectiveness and safety of direct oral anticoagulants (DOACs) in patients with chronic kidney disease (CKD) is a subject of significant interest. Notably, four RCTs have compared DOACs with warfarin for treating VTE in patients with CKD having a creatinine clearance (CrCl) of 30–50 ml/min. The findings show no difference in efficacy and either similar or lower rates of major bleeding, particularly with apixaban and rivaroxaban [24-27]. However, there are limited studies on patients with CrCl <30 ml/min due to their exclusion from many DOAC trials, primarily because of the increased bleeding risk associated with uremia-induced platelet dysfunction and the renal elimination of DOACs, which can lead to drug accumulation and higher bleeding risk [28].

A systematic review and meta-analysis involving 11 VTE-related studies found that among CKD patients receiving treatment for acute DVT, recurrent VTE or VTE-related death was lower in the DOAC group compared to the placebo. The results were inconclusive when compared with VKAs. DOACs appeared to be an effective treatment option for VTE in patients with CKD, but further data are needed. This study compiled trials involving patients with VTE and concomitant CKD and atrial fibrillation (AF), dialysis access, and other cardiovascular diseases. Compared with VKAs, DOACs did differ significantly; however, they reduced the risk of major bleeding [29]. In another study involving six RCTs and 19 observational studies, DOACs reduced the risk of stroke, systemic embolism, and VTE by 22% compared with VKA in patients with CKD, and the risk of major bleeding was also reduced by 17%. In patients with stage 4 and 5 CKD, the efficacy and safety of DOACs were similar to VKA, and overall, DOACs were reported to be more effective and safer than VKA, with apixaban showing particularly prominent advantages [30]. There are several systematic reviews comparing DOACs and warfarin in patients with VTE with concomitant CKD. Considering different CrCl levels, these studies reported that DOACs and warfarin showed similar efficacy in preventing recurrent VTE or VTE-related death. However, DOACs were associated with lower bleeding risk, and its efficacy and safety did not statistically differ across different CrCl levels [31-33].

DOACs in patients with advanced chronic kidney disease (stage 4, 5)

The use of DOACs for patients with advanced CKD has been reported. In a population-based cohort study comparing DOACs and warfarin in patients aged ≥66 years diagnosed with acute VTE concomitant with CKD, no difference in major bleeding was observed between the two groups. Furthermore, there was no difference in major bleeding between DOACs and warfarin across different CKD stages [34]. In a retrospective study utilizing real-world data from a US insurance claims database, 29,790 patients with VTE and CKD were selected, and the results compared the use of apixaban and warfarin. The findings showed that recurrent VTE and major bleeding were associated with lower risk in the apixaban group, and no difference was observed across CKD stages [35]. In a retrospective cohort study, when comparing the use of apixaban and warfarin in patients with advanced CKD (stage 4, 5) who had AF or VTE, it was reported that the risk of major bleeding was significantly lower in the apixaban group after 3 months of treatment. No difference was observed between the two groups regarding stroke and thromboembolism occurrence [28]. Herndon et al. compared warfarin and apixaban in patients with advanced CKD, reporting no difference in major bleeding between both groups, as well as no difference in the occurrence of stroke and VTE [36]. A systematic review of 11 studies evaluating the efficacy and safety of apixaban and warfarin use in patients with advanced CKD discovered that the effects on stroke or systemic embolization and recurrent VTE were similar between the two groups. In addition, it was reported that apixaban had a lower bleeding risk compared with warfarin [37].

Patients with advanced CKD and concurrent VTE pose challenges in treatment decisions, and DOAC use in this population still has limited information available, but apixaban could be considered an option. In one study, when comparing apixaban-based and warfarin-based strategies in patients with VTE and CKD, it was reported that healthcare utilization (hospitalization) was significantly shorter with the apixaban-based strategy. This emphasized the advantages of apixaban [38].

DOACs in patients undergoing dialysis

In patients undergoing dialysis, there is limited research on anticoagulation for VTE. A retrospective cohort study comparing 2,302 and 9,623 patients on apixaban and warfarin, respectively, while undergoing dialysis found that the apixaban group had a lower risk of bleeding, with similar rates of recurrent VTE and all-cause mortality [39]. Conversely, another study indicated that apixaban might increase bleeding risk in patients undergoing dialysis, due to its high plasma protein binding and minimal removal by hemodialysis, leading to drug accumulation. Due to its high plasma protein binding, apixaban is minimally removed by hemodialysis, leading to its accumulation in the serum of patients undergoing dialysis and potentially resulting in increased trough drug levels. Reports suggest that low-dose apixaban can be effective and minimize bleeding in patients with severe CKD or patients on hemodialysis [40,41].

DOACs in elderly patients

Elderly patients often exhibit decreased muscle mass, increased body fat, and declines in renal function and stomach pH, which can affect medication clearance and absorption. They are at a higher risk of bleeding compared to the general population, with older women facing a 20–25% higher risk than men. Elderly patients are often underrepresented in clinical trials due to comorbidities, leading to limited evidence on the optimal anticoagulant for this group [24].

Research on DOACs in older populations shows better efficacy and safety than warfarin in treating VTE for patients ≥75 years. Notably, some reviews have reported no difference in bleeding risk between the two [42,43]. A meta-analysis reported similar efficacy between DOACs and warfarin, with the DOAC group showing significantly lower major bleeding risk [44]. Another meta-analysis found DOACs to be more effective than conventional therapy (warfarin, LMWH) in reducing the risk of VTE or VTE-related death, with a lower risk of major bleeding in patients ≥75 years. In a subgroup analysis of the RECOVER trial comparing dabigatran and warfarin, no differences were found in recurrent VTE, VTE-related death, or bleeding risk for patients ≥75 years [24]. However, individual DOACs showed varying outcomes, and many trials had small sample sizes. Further research is needed to establish effective and safe treatments for this demographic [45].

Conclusion

DOACs are promising for treating VTE in fragile patients with cancer, early stage CKD, and advanced age. However, further research is essential to confirm these benefits, especially in patients with advanced CKD, and caution is needed in patients on dialysis.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

This study was supported by a grant from the Korean Society for Phlebology.

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