Direct Oral Anticoagulants for Treating Fibrin Sheath-induced Central Venous Port System Dysfunction

Abstract

Purpose:

To retrospectively evaluate the safety and efficacy of direct oral anticoagulant therapy for fibrin sheath-induced central venous port system dysfunction.

Material and Methods:

Between May 2023 and February 2024, patients who underwent direct oral anticoagulant therapy for fibrin sheath-induced central venous port system dysfunction were included. The clinical effectiveness, flow confirmation study, central venous port function, and adverse events according to the Common Terminology Criteria for Adverse Events classification were retrospectively reviewed.

Results:

Nine patients were included in the study. The catheter types were open-ended (n = 8) and Groshong (n = 1). All patients had difficulty with aspiration, and one exhibited injection resistance. All patients received edoxaban as direct oral anticoagulant, at doses of 30 mg (n = 3) or 60 mg (n = 6) based on their body weights. After direct oral anticoagulant administration, complete fibrin sheath resolution was confirmed by a flow confirmation study in all cases, with a mean duration of 29 ± 21 days. Concurrently, the central venous port system dysfunction was restored in eight cases. In the remaining one case, direct oral anticoagulant administration was suspended on day 26 due to grade 1 epistaxis; therefore, central venous port system dysfunction remained despite the disappearance of the fibrin sheath. Thus, the clinical success rate was 88.9% (8/9) and fibrin sheath disappearance rate was 100% (9/9), respectively. No grade 3 or higher adverse effect was observed. No recurrence of fibrin sheath-induced central venous port system dysfunction was observed during the mean follow-up period of 133 ± 98 days.

Conclusions:

Direct oral anticoagulant administration can be a potentially effective and safe strategy for managing fibrin sheath-induced central venous port system dysfunction formation.

Introduction

A central venous port (CVP) system is beneficial for long-term chemotherapy and intravenous nutrition management [1]. A fibrin sheath (FS) causes CVP system dysfunction (CVPSD), leading to poor blood aspiration, difficulties with injection, and occasional subcutaneous medication leakage [2]. These dysfunctions are critical issues in the continued use, and function restoration methods include system replacement, snare-stripping, and the use of thrombolytic agents such as urokinase and tissue plasminogen activator (t-PA) [2-5]. In particular, FS treatment with urokinase and low-dose t-PA is minimally invasive and effective. However, at least in Japan, urokinase is difficult to obtain, and low-dose t-PA cannot be easily used due to the cost and insurance coverage issues. Therefore, alternative minimally invasive treatments are required. In recent years, direct oral anticoagulants (DOACs) have been widely used as anticoagulants, and their efficacy in thrombolysis is well-established [6]. Because FS is known to involve thrombus formation in its early stages [7], we have adopted DOAC-based anticoagulant therapy as a new noninvasive treatment approach for FS management. We hypothesized that DOACs are effective and safe in resolving FS-induced CVPSD.

Material and Methods

Study design and population

Between May 2023 and January 2024, flow confirmation studies (FCS) were performed for 17 patients referred to our radiology department to examine CVPSD. “Dysfunction” was defined as difficulty with aspiration and/or resistance or difficulty with injection. The study included patients with FS confirmed by FCS who subsequently underwent DOAC treatment.

This single-center retrospective study was approved by the relevant ethics committee (approval number 2024-123). Opt-out consent was obtained for the retrospective use of patient medical data, and the need for informed consent was waived. The study was performed per the ethical standards as laid down in the 1964 Declaration of Helsinki.

Study outcomes

The primary outcome was restoration from the CVPSD as a clinical success. The secondary outcome was the disappearance of the FS in the FCS. Adverse events (AEs) were attributed to DOACs by physicians and graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

Flow confirmation study

The FCS was conducted to determine the cause of CVPSD. Additionally, if DOAC therapy was administered for FS, the FCS was repeated every 1-4 weeks until FS disappearance or the discontinuation of the medication. Fluoroscopy was used to confirm the absence of device fracture and ensure the correct positioning of the CVP system. Subsequently, a slow injection of 5 mL of heparinized saline solution was administered through the port chamber using a non-coring needle. If flow preservation was observed, 5 mL of the contrast agent (Iopamidol 370 mg/mL) was injected, followed by runoff depiction using digital subtraction angiography. FS was defined as the retrograde tracking of the contrast agent along the catheter wall and the pseudo-enlargement of the catheter [2, 8].

DOAC administration protocol

All patients were orally administered edoxaban (Lixiana^Ⓡ, Daiichi Sankyo Company, Tokyo, Japan) as DOAC. The dosage was set at 30 mg per day for patients weighing <60 kg and 60 mg per day for those weighing ≥60 kg. We recommended to an attending physician discontinuing DOAC administration once the FS has been resolved. However, the final decision regarding the duration of drug administration was made by the physician.

Statistical analysis

Data are summarized as mean ± standard deviation for quantitative variables and frequencies with percentages for categorical variables. The clinical success rate, FS disappearance rate, and incidence of grade <3 or grade ≥3 AEs were presented as percentages. Microsoft Excel for Microsoft 365 MSO version 2407 (Microsoft, Redmond, WA, USA) was used for statistical analyses.

Results

The characteristics of the patients and the CVP systems are presented in Table 1. Nine patients (3 men and 6 women; mean age, 63.9 ± 13.3 years; age range, 44-82 years) with FS-induced CVPSD were included. The catheter types were open-ended (n = 8) and Groshong (n = 1). Specifically, the CVP systems used were seven Dewx Eterna with open-ended catheters (Terumo, Tokyo, Japan), one P-U Cellsite port with an open-ended catheter (Toray Medical, Tokyo, Japan), and one microneedle port with a Groshong catheter (Nipro, Osaka, Japan). All patients were using CVP for intravenous chemotherapy for abdominal cancers, including colon cancer (n = 5), appendiceal cancer (n = 1), rectal cancer (n = 1), ovarian cancer (n = 1), and pancreatic cancer (n = 1). One patient was concomitantly taking aspirin orally. All CVP systems had difficulty with aspiration, and one exhibited injection resistance. CVPSD occurred 541 ± 364 days after implantation. The duration from the most recent use to FS diagnosis was 15 ± 8 days.

Table 1.

Characteristics of Patients and Central Venous Port System.

Variables		Value
Patient characteristics
Age	Mean ± SD (range)	63.9 ± 13.3 (44-82)
Sex	Male/Female	3/6
Body weight	<60 kg/≥60 kg	3/6
Purpose of CVP use	Chemotherapy for solid malignancy	9
Malignancy origin	Colon/Appendix/Rectum/Ovary/Pancreas	5/1/1/1/1
Concomitant anticoagulant/platelet medication	Aspirin/None	1/8
CVP system characteristics
Catheter type	Open-ended/Groshong	8/1
Catheter dwell time (days)	Mean ± SD (range)	541 ± 364 (77-1,212)
Dysfunction	Difficulty with aspiration/Injection resistance	9/1
Duration since last use (days)	Mean ± SD (range)	15 ± 8 (5-28)

CVP: central venous port; SD: standard deviation

Data related to DOAC therapy are summarized in Table 2. All patients received edoxaban at doses of 30 mg (n = 3) or 60 mg (n = 6), based on the patient's body weight. Eight patients completed the oral treatment, with all of them manifesting CVP function restoration 28 ± 21 days, and the FCS confirmed FS disappearance (Figure 1). In patients who started DOAC within 3 days after the diagnosis of dysfunction (n = 7), the mean interval to functional restoration was 19 days, while in the patient who started on day 14 (n = 1), this interval was 81 days. The remaining patient, who commenced DOAC treatment on the 9th day after the diagnosis of dysfunction, experienced mild epistaxis (grade 1; NCI-CTCAE ver. 5.0) and discontinued DOAC on the 25th day because of concerns about hepatic encephalopathy-related falls. Although the FCS on the 40th day after the onset of DOAC treatment confirmed FS disappearance, difficulty with aspiration and injection resistance persisted. Thus, the clinical success rate of the treatment was 88.9% (8/9), and the FS disappearance rate was 100% (9/9). No additional treatments were performed for the residual dysfunction.

Table 2.

Summary of DOAC Therapy for Fibrin Sheath Induced Dysfunction.

Variables		Value
Restoration of dysfunction		8 (88.9%)
Disappearance of fibrin sheath		9 (100%)
Medication period until disappearance of fibrin sheath (days)	Mean ± SD (range)	28 ± 21 (9-83)
Adverse event (CTCAE ver. 5.0)	≥ grade 3	0
	< grade 3	1

CTCAE: Common Terminology Criteria for Adverse Events; DOAC: direct oral anticoagulant

Figure 1.

A woman in her fifties with appendiceal cancer and peritoneal dissemination. (a) Dysfunction with poor blood aspiration occurred 3.1 years after central venous port (CVP) placement, and a flow confirmation study (FCS) diagnosed the cause as a fibrin sheath (FS) (arrows). (b) Two weeks after starting oral edoxaban at a dose of 30 mg/day, the FCS showed that the FS had shrunk and partially dissolved (arrows). (c) Four weeks after drug administration, the FCS showed complete FS disappearance, and the CVP function was restored.

Five of the eight patients discontinued DOAC treatment immediately after FS disappearance, with a mean duration of administration of 43 ± 23 days. The remaining three patients continued DOAC treatment during the follow-up period as determined by the attending physician. No CVPSD recurrence occurred during the mean follow-up period of 133 ± 98 days. In the evaluation, according to CTCAE ver. 5.0, the main AE observed was grade 1 epistaxis in one case, and there were no cases with grade 3 or higher AE.

Discussion

This study demonstrated that DOAC administration is a potentially effective and safe treatment for FS-induced CVPSD. Previous studies have reported success rates for central venous catheter function restoration using urokinase or t-PA between 87% and 100% [2-4, 9, 10], which are consistent with our success rate.

The FS, a so-called catheter-related sheath, is a protein sleeve that forms around various central venous catheters [7, 11]. Immediately after catheter placement, thrombi start to form at the catheter tip due to intravascular protein and cell deposition. Within 24 hours, albumin, lipoproteins, and fibrinogen form a protein sleeve around the catheter. This process leads to the aggregation of coagulation factors and platelets, forming an FS that envelops the catheter [7]. CVPSD occurs when the FS covers the catheter tip. Therefore, if dysfunction is detected early, it is likely that the sheath near the tip contains early-stage thrombi. Fibrin degradation requires thrombolytic agents that convert plasminogen to plasmin. However, we hypothesized that anticoagulants might be effective during the early stage of FS formation, including early thrombi.

Since 2010, DOACs have rapidly replaced the traditional anticoagulant warfarin, and they have rapidly become more widely used. Currently, they are widely used for treating acute pulmonary embolism and/or deep venous thrombosis, non-valvular atrial fibrillation, and venous thromboembolism prevention during the perioperative period [6]. Clinical trials have demonstrated that DOACs are at least as effective as warfarin in thrombosis prevention for most indications and are less likely to be linked with severe bleeding complications [12, 13]. Furthermore, because DOACs do not require frequent dose adjustments, prothrombin time-international normalized ratio monitoring, or dietary restrictions, patients are likely to reduce the burden of treatment. The efficacy and safety of DOACs for FS-induced CVPSD has not been well investigated; however, the safety of DOACs is presumed to be comparable to their administration for other thromboses. All patients in this study received edoxaban as the DOAC, selected by the attending physicians, likely based on prior clinical experience with other thromboses and the convenience of once-daily dosing. As demonstrated in this study, DOACs are effective in treating FS-induced CVPSD. However, in a patient who was administered DOAC 14 days after the diagnosis of dysfunction, the interval to functional restoration (83 days) was longer than in other cases (mean 19 days). Although this single finding cannot establish a causal relationship, it may suggest that the timing of initiation could influence outcomes.

In this study, recurrence of CVPSD was not observed during the follow-up period. In previous studies, the 3-month patency rate after thrombolytic therapy for FS-induced CVPSD was 84%-87.5% [2, 9]. Another study on the infusion of urokinase for FS-induced CVPSD indicated that the mean interval until dysfunction recurrence was 42 days [4]. Although the follow-up period in this study (average: 133 days) was not sufficient, the recurrence rate appeared to be comparable to (or even lower than) those reported in previous studies.

In our study, no upper limit was set for the duration of DOAC administration. The appropriate duration of DOAC therapy for FS has not been well investigated. However, considering that the standard duration of anticoagulant therapy for venous thromboembolism is 3 months [14]; 3 months would be considered as the upper limit. The inefficacy of DOAC during this interval may indicate the formation of a resistant FS, in which case alternative treatment options should be considered.

To our knowledge, there is a paucity of studies on the effectiveness of anticoagulant therapy for the prevention of FS formation. Linch et al. [15] reported that warfarin or heparin therapy could not prevent FS formation in dialysis catheters. Although the result cannot be uniformly applied to the CVP system or DOAC administration, the persistent use of DOAC for FS recurrence prevention may be preferable to avoid, considering the lack of sufficient evidence and the prevention of hemorrhagic complications.

Nevertheless, this study has some limitations. First, it was a retrospective study with no reference group. Second, the sample size was relatively small, and the follow-up period was relatively short. Third, there was a bias in the types of CVP devices used, and the administered DOACs were limited to a single type.

Conclusion

Anticoagulant therapy with DOAC for FS-induced CVPSD may be a potentially effective, safe, and less burdensome alternative to thrombolytic therapy.

Author Contributions

SN: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing − original draft, Writing − review & editing. HK: Conceptualization, Methodology, Writing − original draft, Writing − review & editing. MH: Investigation, Writing − review & editing. SK: Methodology, Investigation. Writing − review & editing. YN: Investigation, Writing − review & editing. NK: Investigation, Writing − review & editing. TA: Investigation, Writing − review & editing. TK: Investigation, Writing − review & editing. MA: Investigation, Writing − review & editing. TS: Investigation, Writing − review & editing. HK: Super Vision, Writing − review & editing. NM: Super Vision, Writing − review & editing. MM: Conceptualization, Super Vision, Writing − review & editing.

Conflict of Interest

Hiroshi Kawada received honoraria for lectures from TERUMO.

Nobuhisa Matsuhashi and Masayuki Matsuo received honoraria for lectures from TERUMO and Daiichi Sankyo. Nobuhisa Matsuhashi's institution received Grant and Research Funding from Daiichisankyo, and Grant from TERUMO and Toray Medical.

The other authors have no relevant conflicts of interest to disclose.