Comparative efficacy of long-term anticoagulation in patients with iliofemoral acute deep vein thrombosis treated with pharmaco-mechanical catheter-directed thrombolysis

Amac: Derin ven trombozu (DVT) tedavisi icin farmakomekanik katater aracili trombliz (FMKAT) yapilan hastalarda; vitamin K antagonistlerini(VKA), dusuk molekul agirlikli heparini (DMAH) ve direk oral antikoagulan ajanlari (DOAK) farmakolojik profilllerinin stabilitesine, semptomatik rekurren venoz tromboembolik, major kanama ve klinik fayda oranlarina gore karsilastirmayi hedefledik. Gerec ve Yontemler: Ocak 2019 ile Haziran 2019 tarihleri arasinda klinigimizde akut iliofemoral DVT tanisi ile FMKAT yapilan ve uzun donemde apixaban (Pfizer, Turkiye) tedavisi ile takip edilen 112 hastanin verileri toplandi. (Grup 1- DOAK) Kontrol gruplarinin datalari ise Ocak 2017 ile Aralik 2018 tarihleri arasinda yine klinigimizde akut iliofemoral DVT tanisi ile FMKAT yapilan ve uzun donemde DMAH (Tinzaparin, Abdi Ibrahim Ilac, Turkiye) tedavisi (Group 2-DMAH; N=119) ve VKA(Coumadin, Eczacibasi Ilac, Turkiye) tedavisi (Grup 3- Kontrol N=111) hastalardan toplandi. Bulgular: VKA tedavisi ile takip edilen hastalarda 3.aydan baslayip 1 yila kadar ki takip surelerinde belirgin oranda tedaviye uyumsuzluk saptandi. Patens oranlari %70'in altindaydi. VKA hastalarinin %32'si yil sonunda terapotik dozlarda degildi. Likert skalalari, Villalta/VCCS ve VEINES-QOL-Sym skorlama sistemlerinin sonuclari klinik sonuclar ile uyumluydu. Sonuc :Bu calisma DOAK'larin DVT hastalarinda tedavi icin DMAH ve VKA'lara mantikli bir alternatif secenek oldugunu gosterdi. DOAK tedavisinin DVT hastalarinda standart bir tedavi olarak tercih edilebilmesi icin bizim elde ettigimiz sonuclari destekleyecek genis kapsamli klinik calismalarin sonuclari beklenmektedir


Introduction
Venous thromboembolism (VTE), which comprises deep venous thrombosis (DVT) and pulmonary embolism (PE), is a significant cause of morbidity and mortality worldwide.
Standard treatment of VTE, using low-molecular-weight heparin (LMWH) overlapped with vitamin K antagonists (VKAs), is effective but requires frequent laboratory monitoring and has the potential for multiple drug and dietary interactions. In recent years, novel treatment strategies with direct oral anticoagulants (DOACs) have been increasing in popularity and availability [1,2].
Post-thrombotic syndrome (PTS) is a chronic complication of DVT, which develops in 20% to 50% of patients. PTS arises from a combination of venous outflow obstruction, venous hypertension, valvular incompetence, and secondary calf muscle pump dysfunction leading to ambulatory venous hypertension.
PTS results in substantially increased healthcare costs and significantly impaired quality of life. Little is known about effects of different anticoagulants on PTS development [3].
Several studies have shown that average patients spend more than 20 % of their time below the therapeutic range during treatment with VKA. It is confirmed that the therapeutic intensity of VKA treatment is an essential determinant for development of PTS since the time spent beneath the therapeutic range is associated with PTS development [4][5][6]. Furthermore, a systematic review found a significantly lower rate of PTS in patients treated with LMWH alone compared to patient treated with LMWH followed by VKA [7].
DOACs approved for treatment of VTE have a stable pharmacological profile and thereby could overcome the disadvantages of VKA. However, the risk of PTS in DVT patients treated with DOACs is unknown [8].
Pharmaco-mechanical catheter-directed thrombolysis (PMCDT) refers to mechanical thrombus disruption concomitant with fibrinolytic therapy, offering a lower dosage of thrombolytic agent, a shorter procedure and an improvement in outcomes.
PMCDT is an alternative option for treatment of DVT and decreasing the incidence of PTS. The patients who are most likely to benefit have iliofemoral DVT, symptoms for <14 days, good functional status, life expectancy of >1 year, and a low risk of bleeding. More rapid thrombus resolution is associated with the improved valvular function [9][10].
Long-term treatment is preconized in a significant proportion of the patients with VTE. However, limited direct/indirect comparisons are available to appropriately weight the benefit/ risk ratio of the diverse treatments available.
We aimed to compare the stability of pharmacologic profile,   All patients were symptomatic upon admission and after calculating the Wells score [11], venous duplex ultrasonography was performed for initial diagnosis. The extent of the thrombus and the calculation of the Marder score [12] was evaluated and calculated by initial contrast venography.

Technique (PMCDT)
All procedures were performed under local anesthesia in single-
At the end of the procedure, patients received one of the three regimens before discharge.

Follow-up and Outcome Assessments
All patients were evaluated before discharge and were scheduled to return for ambulatory follow-up visits at 1, 3, 6 and 12 months after the procedure except for an emergency.
At these visits, physical examination, doppler ultrasonography, INR (VKA patients) and anti-Xa (LMWH and DOAC patients) levels were performed.
Definitions of major and minor complications, anatomical success, early and late re-thrombosis, recurrent DVT, anatomical patency were evaluated within the scope of

Reporting Standards for Endovascular Treatment of Lower
Extremity Deep Vein Thrombosis [14].
Early symptom relief, was evaluated by assessing leg swelling using standardized leg circumference measurement through 10 cm below the tibial tuberosity of the index leg and leg pain using a 7-point Likert Scale which both instruments were previously reported as effective and inexpensive to document changes in limb symptomatology [14].
To grade the severity of chronic venous disease and its impact on QOL, Venous Insufficiency Epidemiological and Economic Study Quality of Life measure (VEINES-QOL) evaluation were performed at 12th -month control [17].

Statistical analysis
All statistical analyses were conducted using SPSS 18

Results
Baseline evaluation of patients on hospitalization is summarized in Table 1.
Early peri-procedural data is listed in Table 2.
No complications occurred in terms of pulmonary embolism or bleeding during early period. Minor bleeding as subcutaneous hemorrhage at the access site was observed in 2, 3 and 2 patients in Groups 1,2 and 3 respectively.
Follow-up data of patients is documented in Table 3. 4 patients in DOAC group were excluded for not being able to complete 12-month data.

Discussion
The use of VKAs like warfarin is recommended by guidelines in the medical treatment of VTE. However, it is limited by the need for frequent monitoring of INR, drug interactions, drugfood interactions, prior bridging with inpatient parenteral anticoagulation before commencing, as well as the risk of bleeding with its use [18]. Conversely, DOAC does not require regular INR testing and dose adjustments, while still remaining effective and safe in the treatment of VTE, with comparable rates of clinically significant bleeding and mortality [6]. While anticoagulation probably plays an important role, evidencebased data is scarce and optimal anticoagulation treatment of DVT to prevent PTS development is still unknown. In treatment with VKAs, sub-therapeutic anticoagulation in the first few weeks is associated with a higher incidence of PTS development. Analysis of long-term LMWH treatment alone showed a lower incidence of PTS compared to standard treatment with warfarin.9 Together with the observation that the severity of symptoms and signs four weeks after acute DVT is associated with subsequent PTS development, these findings suggest optimal anticoagulation treatment in the first weeks after acute DVT is crucial in preventing the development of PTS later in the course of the disease [19].
Sub-therapeutic anticoagulation might maintain thrombin production, thus promoting coagulation, reducing natural clot lysis and causing venous wall damage, which could lead to PTS development in the long-term. Therefore, DOAC, with their rapid onset and stable pharmacokinetics, could lower the incidence of PTS in comparison to warfarin [20][21].
We designed this study comparing three different regimens after PMCDT, in which patients were completely (>90%) cleaned from the existing thrombi load verified by ultrasonography and venography and continued a thorough follow-up to one year.
As demonstrated in Table 3, our patients treated with VKA showed a significant incompliance starting from third month up to one year. It is known that patients treated with VKA and monitored in a community setting have a lower adherence than patients in a trial setting. Considering that reduced treatment burden and regimen complexity are associated with better compliance, DOAC patients might have a better adherence in clinical practice and thereby contributing to better long-term clinical outcomes like PTS, especially in settings where INR control is suboptimal [22][23].
Patency rate diminished significantly below 70%. Major 319     VEINES-QOL-Sym score was significantly better in DOAC group with respect to VKA in 6th and 12th month controls and LMWH in 12th month controls, demonstrating better quality of life.
Our study has also some limitations. The main limitation of the study was the retrospective nature of the study which we tried to balance with propensity score matching.
The majority of PMCDT procedures in studies including our study were performed via popliteal approach. This approach has a possibility to leave a burden of residual occlusive thrombus in the popliteal vein, thereby leading to a possible increment in symptoms of PTS. We could have designed another group studying posterior tibial access to compare. Residual thrombus load and the patency of outflow veins were evaluated by venography in our study. But we know that, assessment of the patency of iliofemoral veins should be based on IVUS rather than venograms alone, because even small amounts of thrombus may enhance inflammatory reaction and thereby cause recurrent DVT and/or PTS. Due to reimbursement criteria in our country, we could not use IVUS in our study.

Conclusion
Our study highlights the potential role of DOAC as a reasonable alternative to VKAs/LMWH in the long-term anticoagulation strategy for DVT. DOAC appears to be similar in efficacy, and may potentially result in fewer major bleeding events, rehospitalization, better compliance and stability in therapeutic range leading to better quality of life. This is one of the first reports comparing three popular regimens in the setting of PMCDT. We await larger clinical trials to support these findings and establish the role of DOAC as the standard of care for patients with VTE.