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Corresponding author. Academic Section of Vascular Surgery, Division of Surgery, Department of Surgery & Cancer, Imperial College London, 4 East, Charing Cross Hospital, Fulham Palace Road, Hammersmith, London W6 8RF, UK.
Deep venous stenting is increasingly used in the treatment of deep venous obstruction; however, there is currently no consensus regarding post-procedural antithrombotic therapy. The aim of the present study was to determine the most commonly used antithrombotic regimens and facilitate global consensus.
Methods
An electronic survey containing three clinical scenarios on venous stenting for non-thrombotic iliac vein lesions, acute deep vein thrombosis (DVT), and post-thrombotic syndrome was distributed to five societies whose members included vascular surgeons, interventional radiologists, and haematologists. The results of the initial survey (phase 1) were used to produce seven consensus statements, which were distributed to the respondents for evaluation in the second round (phase 2), along with the results of phase 1. Consensus was defined a priori as endorsement or rejection of a statement by ≥ 67% of respondents.
Results
Phase 1 was completed by 106 experts, who practiced in 78 venous stenting centres in 28 countries. Sixty-one respondents (58% response rate) completed phase 2. Five of seven statements met the consensus criteria. Anticoagulation was the preferred treatment during the first 6–12 months following venous stenting for a compressive iliac vein lesion. Low molecular weight heparin was the antithrombotic agent of choice during the first 2–6 weeks. Lifelong anticoagulation was recommended after multiple DVTs. Discontinuation of anticoagulation after 6–12 months was advised following venous stenting for a single acute DVT. No agreement was reached regarding the role of long-term antiplatelet therapy.
Conclusions
Consensus existed amongst respondents regarding anticoagulant therapy following venous stenting. At present, there is no consensus regarding the role of antiplatelet agents in this context.
This is the first study to investigate antithrombotic practices after venous stenting, from a large body of venous stenting experts. Using the Delphi methodology consensus was achieved on a number of important issues, including the use of anticoagulation, duration of treatment, and thrombophilia screening. It is hoped that the findings of this consensus will facilitate clinical decision making in new units and guide future research.
Introduction
Obstructive lesions of the deep venous system are an increasingly recognised cause of chronic venous disease.
Iliofemoral venous stenosis or occlusion can occur as a result of post-thrombotic or non-thrombotic iliac vein lesions (May–Thurner syndrome), or external compression, for example by a pelvic mass.
In recent years, venous stenting has risen to prominence as the intervention of choice to relieve the symptoms and signs of iliofemoral obstruction.
A number of international guidelines now recommend venous stenting for patients with iliac or common femoral vein obstruction who suffer from venous claudication, ulceration, or severe oedema resistant to compression (Grade 1B, Class II).
The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American heart association.
Although a number of studies have focused on technical factors associated with stent occlusion, there is paucity of research examining the role of antithrombotic therapy in maintaining stent patency.
The lack of consensus on this issue is reflected by the varied antithrombotic therapies reported in the literature on outcomes of venous stents and the paucity of recommendations amongst international guidelines.
Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
For example, the American College of Chest Physicians' guidelines recommend anticoagulation for at least 3 months in patients following deep vein thrombosis (DVT) thrombolysis and venous stent placement; however, no specific guidelines exist for antithrombotic therapy following venous stenting for chronic venous obstruction.
Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
The aim of this study was to identify international antithrombotic practices following venous stenting and to determine whether consensus could be achieved using Delphi methodology.
Materials and methods
Study design
The Delphi method is a technique used to gain expert consensus on a particular issue. It is an iterative process, which involves a series of questionnaires and controlled feedback.
The survey results are collated, analysed, and fed back to the participants until an a priori consensus is reached. The benefits of the Delphi approach have been extensively described in the literature.
Briefly, it obviates the need for experts to meet physically, which enables international participation and rapid turnaround to facilitate a group consensus, despite uncertainties.
Phase 1
Three scenarios were presented, which included non-thrombotic iliac vein lesion (mentioned as “May–Thurner syndrome” in the clinical scenario; case 1), acute iliofemoral DVT with a residual obstruction after thrombolysis (mentioned as “May–Thurner lesion” in the clinical scenario; case 2), and post-thrombotic syndrome (case 3). Brief descriptions of the scenarios are given in Figure 1, Figure 2, Figure 3. The choice of cases was based on a literature review of the indications for venous stenting and the authors' clinical experience. Feedback from four venous stenting experts was sought and resultant changes were made to content, wording, and response options before the survey was circulated. A web based electronic survey tool (SurveyMonkey; https://www.surveymonkey.co.uk/r/deepvenousstenting) was used to design and distribute the survey. For each scenario, the respondents were asked to provide the details of their chosen antithrombotic regimen, including the type of agent, duration, and any other relevant details. Demographic details and caseloads of the respondents were recorded to ensure that clinicians without a special interest in venous stenting were not included in the study.
Figure 1The choice of antithrombotic regimens in scenario 1. Note. LWMH = low molecular weight heparin; DOAC = direct oral anticoagulant.
An invitation to take part in the study was e-mailed to the members of the following societies: the European Venous Forum, the British Society of Interventional Radiology, the Australasian College of Phlebology, the European Society for Vascular Surgery, and the British Society for Haematology. Invitations were also sent to the experts based on the recommendations of the respondents following completion of the phase 1 survey. The phase 1 survey took place between 5 April 2017 and 5 June 2017.
Phase 2
Analysis of responses from the initial survey was used to generate seven consensus statements regarding the antithrombotic regimens in the above described scenarios. In the follow-up survey, respondents were provided with the information regarding the results of phase 1 and were asked to endorse or reject the proposed consensus statements. In addition, a question on the most important factors regarding the choice of anticoagulants was included. The invitation to complete the survey was emailed directly to the members of the panel on 23 June 2017. A reminder email was sent to the non-respondents after 2 weeks.
Data analyses
Data were analysed using Excel (Version 15.0; Microsoft, Redmond, WA, USA). Free text responses from phase 1 were analysed and coded into groups, which were then presented as frequencies. All responses to phase 2 questions were binary and expressed as percentages. Consensus was defined a priori as two thirds (≥67%) of respondents either endorsing or rejecting a statement. The effect of geographical location and case volumes on participant responses was determined using the chi-square test, with the statistical significance level set at a p value < .05.
Results
Respondent demographic characteristics
The phase 1 survey was completed by 106 respondents who practised in 78 centres in 28 countries (Table 1). The majority of participants were from the UK (n = 50 [48%]) and continental Europe (n = 33 [31%]). Half of the respondents were vascular surgeons (n = 53), 38% were interventional radiologists (n = 40), and 12% were haematologists (n = 13). The median number of venous stenting procedures carried out in each centre was three per month (interquartile range 1–10).
Table 1Demographic characteristics of the phase 1 respondents.
Deep venous stenting of a non-thrombotic iliac vein lesion
In case 1, there was considerable variation in the reported antithrombotic regimens. Anticoagulation with low molecular weight heparin (LMWH) and vitamin K antagonists (VKA), or direct oral anticoagulants (DOACs) for 6 months was reported by 28% and 15%, respectively (Fig. 1). Twenty-five per cent reported the use of antiplatelets in conjunction with anticoagulants, whereas 16% opted for antiplatelet therapy without anticoagulation. Twelve per cent reported the use of follow-up imaging to guide the duration of anticoagulation.
Deep venous stenting following acute iliofemoral DVT
In case 2, the reported antithrombotic therapies were varied. Anticoagulation with VKA for 12 months was the most commonly reported regimen (29%; Fig. 2). Antiplatelets were used in conjunction with either DOACs or VKA by 27%. Lifelong anticoagulation with either VKA or DOAC was chosen by 12%.
Deep venous stenting in the context of post-thrombotic syndrome
For case 3, a number of antithrombotic therapies were reported. A third of respondents employed lifelong anticoagulation with VKA, with a further 19% choosing lifelong anticoagulation with DOACs (Fig. 3). Discontinuation of anticoagulation between 6 and 12 months was reported by 35%. The use of antiplatelet agents following discontinuation of anticoagulation was chosen by 25%.
The effect of case volume and geographical location on antithrombotic regimens
To determine whether the number of procedures performed in each centre influenced the choice of antithrombotic regimens, the survey respondents were split into two groups based on the median number of monthly procedures. Similar responses across all three scenarios were observed between the respondents from centres with <4 venous stenting procedures per month versus those performing four or more (Table S1; see Supplementary Material). Similarly, the choice of antithrombotic regimens was compared between the respondents from the UK and other countries, with no statistically significant differences detected between the two groups (Table S1).
Phase 2 survey summary of results: consensus statements
Sixty-one of 106 respondents (58% response rate) completed phase 2. The geographical distribution of the respondents was comparable to phase 1 (UK 40%, continental Europe 29.5%, Australasia 8.2%). Five of seven statements achieved the definition of consensus (Figure 4, Figure 5). Seventy-two per cent of respondents preferred anticoagulation to antiplatelet therapy following venous stent placement for compressive non-thrombotic iliac vein lesion. LMWH was chosen as the anticoagulant of choice in the first 2–6 weeks after venous stenting by 67%. Regarding the discontinuation of anticoagulation, 67% believed thrombophilia screening was essential after a first DVT, and 87% of respondents were in support of stopping anticoagulation in patients with a single acute DVT after 6–12 months, given a satisfactory stent appearance on ultrasound and a negative thrombophilia screen. Eighty-five per cent opted for lifelong anticoagulation therapy following stenting for multiple DVTs. No consensus was reached regarding the role of antiplatelet therapy following venous stenting. Fifty-five per cent believed lifelong antiplatelet therapy was needed in patients with compressive iliac vein lesions. Forty per cent supported the statement that antiplatelet agents have important clinical benefit in addition to anticoagulation in patients with multiple DVTs and post-thrombotic syndrome. No statistically significant differences were found when responses to the seven consensus statements were compared between the participants from the UK and other countries (chi-square, p > .05).
Factors influencing the choice of antithrombotic agents
The top three factors influencing choice of antithrombotic therapy were evidence base (56%), followed by minimisation of the time a patient was sub-therapeutic (51%), followed by patient convenience (49%) (Fig. 6).
Figure 6The most important factors reported when choosing an antithrombotic agent. Note. INR = international normalised ratio.
Using the Delphi technique the opinions of 106 experts were obtained, and consensus was established on five important issues regarding antithrombotic therapy following venous stenting.
The initial survey results revealed highly varied choices of antithrombotic agents in all three case scenarios. VKAs were the most commonly used agents; however, almost a third reported the use of DOACs. This is in contrast to the majority of the large published case series in venous stenting, which almost exclusively used VKA.
The finding probably reflects a change in anticoagulation practices, which have seen a major shift towards the use of DOACs, despite the fact that DOACs are not licensed for use following venous stenting. In small case series (n = 9), Langwieser et al. reported 100% stent patency rates and no major adverse events at 14 months in patients treated by the combination of rivaroxaban and clopidogrel following iliofemoral venous stenting.
The consensus on the duration of anticoagulation was reached with overwhelming majority. Eighty-nine per cent of the responders supported the discontinuation of anticoagulation in patients with non-thrombotic compressive iliac vein lesions after 6–12 months given stent appearances on ultrasound were satisfactory. This is likely to be based on the fact that the incidence of stent thrombosis plateaus after 6–12 months once endothelialisation occurs and that these patients have a lower incidence of thrombophilia.
Likewise, consensus was reached (67%) regarding the use of LMWH during the initial treatment period, in case early re-intervention was required. Indefinite anticoagulation in patients receiving venous stents following multiple DVTs was supported by 85% and reflects the recommendations set out by guidelines regarding the treatment of recurrent VTE.
Consensus (67%) was also achieved regarding thrombophilia screening following first DVT to guide anticoagulation duration. A significant proportion of patients (30–50%) who required venous stenting for iliofemoral DVT have been reported to have thrombophilia.
Although current National Institute for Health and Care Excellence guidelines advise against testing for thrombophilia following a provoked DVT without a positive family history, the participants (nearly half interventional radiologists) in this survey felt otherwise, possibly as a result of placing a prosthetic thrombogenic implant in a young patient. The results from case series and registries not using thrombophilia screening in the future will hopefully guide the community as to whether there is a real need for detailed coagulation profiling after first DVT lysis and stenting, or whether this is a minor problem.
The role of antiplatelet agents following venous stenting appears to be unclear, based on the findings of this survey. The findings are in line with the systematic review by Eijgenraam et al. in which only four of 12 studies reported antiplatelet use in venous stenting procedures.
Although antiplatelets have been shown to be beneficial in preventing restenosis of arterial stents, these effects cannot necessarily be extrapolated to venous stents.
Antithrombotic therapy in peripheral artery disease – antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
In an experimental porcine model, McBane et al. demonstrated that aspirin and clopidogrel failed to prevent venous stent thrombosis, in contrast to factor Xa inhibitor, which completely inhibited thrombosis of venous stents.
There are several strengths of this study. Considering that venous stenting is practised only in tertiary centres, a relatively large number of multidisciplinary experts involved in venous stenting contributed to the survey. The use of Delphi methodology ensured that the information collected from the respondents was independent from dominant individuals.
Limitations
Several limitations of this study need to be mentioned. It was not possible to determine the response rate in phase 1 as the survey was sent out to all members of the societies, which represents an unknown denominator. The respondents were predominantly from the UK and Europe, which may represent a source of bias. However, the subgroup analyses did not show any significant differences in the choice of antithrombotic therapy across different geographical locations, suggesting external validity of the findings.
The Delphi method also has limitations. One of the main criticisms of the Delphi approach is that an investigator has a disproportionate control over the breadth and direction of the topic under investigation.
To address this, participants were intentionally allowed to describe their chosen antithrombotic regimens using free text in phase 1. As a result, the consensus statements were largely driven by free text data retrieved from the respondents, rather than the investigators' choices. Other criticisms of the Delphi approach are that, although responses are fed back to all participants, there is a lack of debate before consensus is achieved. Furthermore, no gold standard threshold for the definition of consensus exists in the literature; therefore, the choice of a two thirds majority might appear arbitrary.
However, it was ensured that the standard was set at the protocol stage, prior to the commencement of the study, as per Delphi methodology guidelines, and the threshold value was comparable to those in previously reported studies.
It is entirely possible to read this paper without, in fact, setting a threshold for consensus at all and simply using the voting as an expression of strength of feeling in the venous stenting community.
Finally, the definition of “expert” is a complex one and extends beyond numbers of cases and years of experience. Experts in venous stenting were defined as doctors selecting, stenting, or giving post-procedure follow-up for those undergoing venous stenting. Whether respondents felt they were “expert” enough to respond was left to their own judgement. However, it was made clear that the survey was intended for experts in this field.
Future work
It is hoped that the results of the present consensus study will facilitate the writing of specific guidelines on antithrombotic therapies following deep venous stenting, which are currently largely lacking. While evidence from the randomised trials is awaited, detailed guidelines on antithrombotic therapy for venous stenting are needed to guide the management of this complex group of patients. The findings of the present study could inform new venous stenting centres and be the basis for future research in three main areas. First, the difference between VKA and DOACs after thrombolysis and stenting, with regard to primary patency needs to be determined. Second, the duration of therapy after DVT lysis and stenting should be investigated. Third, it is important to know whether antiplatelet agents add any benefit over anticoagulants. Venous stenting procedures should also be captured in national vascular registries.
Conclusion
Results from this study indicate that there is consensus on duration of anticoagulation, choice of anticoagulant agents during the initial phase, and thrombophilia screening. While further evidence from controlled studies is awaited, it is hoped that this study will serve as a base for future research and guideline development.
Acknowledgements
We would like to thank the following societies for distributing the survey: the European Venous Forum, the British Society of Interventional Radiology, the Australasian College of Phlebology, the European Society for Vascular Surgery, and the British Society for Haematology. We also thank all the participants who contributed to the survey results. The names of the persons who gave permission to be acknowledged, as part of the consensus group, are listed in Appendix S1 (see Supplementary Material).
Appendix A. Supplementary data
The following are the supplementary data related to this article:
Table S1 Comparison of antithrombotic regimen choices between geographical locations and high and low volume centres.
The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American heart association.
Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed.: American College of Chest Physicians evidence-based clinical practice guidelines.
Antithrombotic therapy in peripheral artery disease – antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines.
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