Protocol of the Reformation study: a prospective, multicenter, randomized controlled trial on the improvement of rheolytic thrombectomy for acute deep vein thrombosis of the whole lower limb by primary popliteal vein thrombosis clearance

Protocol of the Reformation study: a prospective, multicenter, randomized controlled trial on the improvement of rheolytic thrombectomy for acute deep vein thrombosis of the whole lower limb by primary popliteal vein thrombosis clearance | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Protocol of the Reformation study: a prospective, multicenter, randomized controlled trial on the improvement of rheolytic thrombectomy for acute deep vein thrombosis of the whole lower limb by primary popliteal vein thrombosis clearance Qihong Ni, Xiande Ye, Chunshui He, Hui Zhao, Wensheng Lou, Hui Zhuang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4157062/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction : Pharmacomechanical thrombectomy (PMT) can be a useful treatment for restoring vein patency quickly especially for extensive acute deep vein thrombosis (DVT). However, previous evidence failed to validate the effectiveness of PMT in reducing the incidence of post-thrombotic syndrome (PTS). To address this controversy, the Reformation study aims to improve rheolytic thrombectomy for acute deep vein thrombosis of the lower limb through primary popliteal vein thrombosis clearance. Method and analysis : Reformation is a prospective randomized multicenter trial. It has 160 patients in two groups: the modified access group (80 patients) and the traditional access group (80 patients). The purpose of this study is to assess whether the modified access approach for removing inflow thrombus in a one-stage procedure is more effective in enhancing the success rate of the procedure and reducing the incidence of post-thrombotic syndrome during a 24-month follow-up period, for patients with acute whole limb DVT. Ethics and dissemination : The Reformation study has been registered at www.clinicaltrials.gov (registration number: NCT05286710). The study protocol has been approved by the Institutional review board and Human Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (Approved number: KY2021-067-A). The results will be disseminated by publication in a peer-reviewed journal. Trial registration number : NCT05286710 Protocol version and date : V.1.2, 20 August 2022 Randomized controlled trial Deep vein thrombosis Pharmacomechanical thrombectomy Post-thrombotic syndrome Figures Figure 1 Strengths and limitations of this study 1) To our knowledge, the Reformation study is the first randomized controlled trial to determine whether inflow DVT burden affects the clinical efficacy of PMT in patients with extensive DVT over the long term. 2) This study will provide high-quality evidence for the clinical application of PMT in the treatment of extensive DVT. 3) This study is an evaluator-blind trial. The participants and surgeons cannot be blinded. 4) The 24-month follow-up period is relatively not long enough for evaluating incidence of PTS in DVT patients. 1. Introduction Venous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE). 1 VTE is the third most common cardiovascular disease after myocardial infarction and stroke. 2 – 4 Up to 50% of the patients suffering from DVT will develop post-thrombotic syndrome (PTS), which may be accompanied by major disability. 5 , 6 The pathophysiologic mechanism of PTS involves the development of venous hypertension and venous valve incompetence. Following DVT, serious PTS, including venous ulcers, develops in up to 10% of patients. 7 – 9 The standard strategy for preventing further clot formation and recurrent PE is systemic anticoagulation. 10 – 12 However, this method cannot eliminate existing thrombus, which can result in PTS and venous valvular insufficiency. In contrast, catheter-directed thrombolysis (CDT) directly infuses thrombolytic agents into the occluded vein, reducing systemic drug exposure and the necessary therapeutic dose. Current evidence supports the utility of endovascular methods, such as CDT, which may be useful for patients who have severe symptoms, extensive DVT, high physiologic reserve and long-life expectancy, low bleeding risk, and who do not respond well to initial oral anticoagulation therapy, particularly within the acute time frame of 2–4 weeks after symptom onset. 13 Although there are certain benefits associated with CDT, recent trials such as ATTRACT and CAVA have not been able to confirm them. Moreover, CDT has a relatively longer infusion time, ranging from 8 to 87 hours, which increases the risk of major bleeding during the procedure. 14 – 16 Percutaneous mechanical thrombectomy (PMT) is an alternative method to remove acute DVT. 17 . 18 The AngioJet rheolytic thrombectomy system is one of the most widely used PMT catheters. 19 The system uses high-pressure saline or thrombolytic agent jets to create a pressure gradient based on the Bernoulli effect, which fragments and aspirates the thrombus. Previous comparative case series studies show that PMT has demonstrated potential benefits compared to CDT alone, including lower doses of thrombolytic agents and shorter infusion times. This results in a reduced risk of hemorrhagic events and, in turn, less use of hospital resources. Moreover, owing to newly modified approaches, it is now possible to eliminate DVT in all segments simultaneously. Our previous study demonstrated that using a contra-lateral femoral vein or tibial vein for one-stage inflow DVT removal resulted in a significantly higher rate of thrombus clearance in a single session compared to the traditional ipsilateral popliteal venous approach. 20 Furthermore, patients who required further CDT and PTS treatment at the 2-year follow-up were significantly lower in the modified access group. However, a study conducted by Jeyabalan G et al. revealed that inflow thrombosis did not affect the outcomes of thrombolysis in patients with popliteal and tibial clots who underwent PMT from thrombosed PV access. After treatment, 90% of the patients regained patency of the popliteal vein, but more than 60% of the patients needed additional treatment after PMT. 21 It is uncertain whether removing inflow venous thrombus from the tibial and distal popliteal areas would improve venous drainage, maintain patency, and reduce venous reflux. Although these results are promising, there is still no conclusive evidence from multicenter randomized controlled trials (RCTs) to support them. Therefore, we have initiated the Reformation study to address this controversy by improving rheolytic thrombectomy for acute deep vein thrombosis of the lower limb through primary popliteal vein thrombosis clearance. 2. Methods Study objective The primary study objective is to determine whether removing blood clots in the distal popliteal vein using a modified approach can reduce the incidence of PTS over a 24-month follow-up period in patients with extensive acute DVT involving the iliac and femoropopliteal veins when compared to performing PMT through the traditional approach of the ipsilateral popliteal vein. Secondary objectives include: (a) Patency rate immediately after lonely mechanical thrombectomy. (b) Total time of interventional surgery (Including duration of subsequent catheter-directed thrombolysis). (c) Total dosage of urokinase used for the procedure. (d) Patency rate of lower limb vein at post-interventional 12 and 24 months. (e) Deep venous valve function evaluation by ultrasound at post-interventional 12 and 24 months. (f) Quality of life (QOL) score, venous insufficiency epidemiological and economic study quality of life (VEINES-QOL) score, and European quality of life 5-dimension 5-level (EQ-5D-5L) score at post-interventional 3, 6, 12 and 24 months. (g) Re-intervention rate within 24 months after operation. (h) Treatment rate of catheter-directed thrombolysis after mechanical thrombectomy. The safety outcomes include procedural complications such as hematoma at the puncture site, hemoglobinuria or hemolytic jaundice, bleeding events, and all-cause death during the follow-up period. Study design Reformation is an ongoing, multicenter, randomized, open-label, two-arm controlled trial sponsored by Boston Scientific. The study design, execution, and data analysis are independent of the sponsor. 160 patients will be recruited from and randomized at 9 participating hospitals in China. The first patient was recruited in October 2022. The study protocol has been approved by the Institutional review board and Human Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (Approved number: KY2021-067-A). All participants will provide written informed consent before enrollment. Patients will be randomly allocated in a 1:1 ratio by central stratification and block randomization method to receive either modified or traditional PMT treatment. The patients flow diagram was shown in Fig. 1 . The statistical analyst of this study generates the random allocation table through SAS software. The block length and random allocation table of each center will be kept blind and not be opened during the whole study period. The study was overseen by an independent Data Safety Monitoring Board and was conducted in accordance with Good Clinical Practices. Patient population To be eligible for inclusion, patients must be between 18–75 years old and have a first-time symptomatic DVT involving the iliac and femoropopliteal vein, verified by compression ultrasonography or venography. The study aims to recruit a total of 160 individuals with entire-limb acute DVT. Out of these, 80 participants will be treated with PMT via the contralateral femoral vein, jugular vein or ipsilateral tibial vein, which is referred to as the modified access group. The remaining 80 participants will be treated with PMT via the ipsilateral popliteal vein, which is referred to as the traditional access group. Inclusion Criteria ( Table 1 ) : Table 1 Inclusion criteria We include the patients with all the following criteria: 1) Age between 18–75 years old 2) Acute DVT occurred less than 14 days from the onset of the disease 3) DVT with thrombosis involving the iliac vein, common femoral vein, distal popliteal vein, and/or calf vein 4) The patient must have signed an informed consent form DVT: deep vein thrombosis 1) Age between 18–75 years old; 2) Acute DVT occurred less than 14 days from the onset of the disease; 3) DVT with thrombosis involving the iliac vein, common femoral vein, distal popliteal vein, and/or calf vein; 4) The patient must have signed an informed consent form. Exclusion criteria ( Table 2 ) : Table 2 Exclusion criteria We exclude the patients with either of the following criteria: 1) Patients with a history of DVT in the same lower limb 2) Plasma Creatinine level greater than 180umol/L 3) Patients who are contraindicated for thrombolysis treatment 4) Patients with thrombosis in inferior vena cava 5) Patients who have a known allergy to heparin, low molecular weight heparin, or contrast agent 6) Patients who have participated in a clinical trial within the past three months 7) Women who are pregnant or lactation 8) Patients with other diseases that may interfere with the study or significantly reduce their life expectancy (less than 2 years) 9) Patients with autoimmune thrombopathy 10) Patients who are unwilling or unable to participate in the study DVT: deep vein thrombosis 1) Patients with a history of DVT in the same lower limb; 2) Plasma Creatinine level greater than 180umol/L; 3) Patients who are contraindicated for thrombolysis treatment; 4) Patients with thrombosis in inferior vena cava; 5) Patients who have a known allergy to heparin, low molecular weight heparin, or contrast agent; 6) Patients who have participated in a clinical trial within the past three months; 7) Women who are pregnant or lactation; 8) Patients with other diseases that may interfere with the study or significantly reduce their life expectancy (less than 2 years); 9) Patients with autoimmune thrombopathy; 10) Patients who are unwilling or unable to participate in the study; Conduct of the study Patients who meet the inclusion criteria and do not have any exclusion criteria will be invited to participate in this study. Once they provide written informed consent, they will be assigned randomly assigned to receive PMT treatment through either modified or traditional access. Anticoagulation will begin with full therapeutic anticoagulation with twice-daily weight-based low molecular weight heparin (LMWH) for at least 8 hours, followed by oral anticoagulation therapy for at least 6 months. The oral anticoagulation therapy will be administered through new oral anticoagulants or warfarin (maintaining INR between 2 and 3). Compression stockings, class II, will also be used as a standard adjunctive treatment, daily for 24 months. PMT procedure All endovascular treatments will be done using local anesthesia. Pre-procedure and post-procedure venography from a dorsal foot vein will be conducted to assign a thrombus score to each of the six venous segments (Common iliac, external iliac, common femoral, central femoral, peripheral femoral, and popliteal veins) according to the following criteria: complete occlusion of the venous segment was given a score of 3, substantial occlusion (50–99%) of the venous segment was given a score of 2, partial occlusion (0–50%) of the venous segment was given a score of 1, and a patent venous segment was given a score of 0. Thrombus scores were totaled for each enrolled patient with the potential range of 0 to 18. The degree of thrombus removal was graded by calculating the percentage reduction in the patient's total thrombus score. 22 During the PMT procedure, it is recommended to use a retrievable IVC filter that should be removed 14–21 days after treatment. To establish venous access, ultrasound or venography guidance will be used. For the modified approach, the decision to use contralateral femoral vein, jugular vein or ipsilateral tibial vein access will be at the discretion of the operating interventionist. For the traditional approach, the ipsilateral popliteal venous access will be obtained. Pulse spray thrombolysis using the 6F Angiojet device will initially be employed to treat the occluded veins, with a maximum of 250,000 UI Urokinase administered. After a 15-minute dwell time, the Angiojet catheter will be used to eliminate residual thrombus, by employing the standard mechanical aspiration thrombectomy technique. CDT will be used selectively as needed for residual thrombus, using a multiple-side hole catheter (Angiodynamic, USA), with the maximum allowable CDT duration being 72 hours. During the CDT procedure, hemostasis will be monitored by analyzing hemoglobin, fibrinogen, D-dimer, INR, and platelet counts 3 times a day. The dose of urokinase will be adjusted according to the result of fibrinogen. The effect of treatment will be assessed daily by venography, and Percutaneous balloon angioplasty (PTA) will be performed if the stenosis of the iliac vein diameter is greater than 50%. A stent will be placed if the residual stenosis exceeds 50% after PTA treatment. Outcome evaluation After their intervention, Patients will have follow-up at scheduled 14 ± 7 days, 12 months, and 24 months after their intervention. At 14 ± 7day follow-up, venography will be conducted to evaluate the technical success rate during their return for IV filter removal. At each visit, physicians who are not familiar with the patient's history will conduct a clinical evaluation and a duplex ultrasound (DUS) assessment of the affected lower limb. Additionally, a telephone interview will be conducted 3, 6, and 18 months after the intervention. (Table 3 ) Table 3 Enrollment, intervention and follow-up schedule Enrollment (Day − 1) Allocation (Day 0) Follow-up (14 days) Follow-up 3 months Follow-up 6 months Follow-up 12 months Follow-up 24 months Eligibility screen × Informed consent × Allocation × Venography × × Clinical evaluation × × CEAP classification × × PTS scale by Villalta score × × Duplex ultrasound assessment × × Venous patency × × Deep venous valve function × × EQ-5D-5L score × × × × QOL score × × × × VEINES/QOL score × × × × CEAP: clinical-etiologic-anatomic-pathophysiologic; PTS: post-thrombotic syndrome; EQ-5D-5L: European quality of life 5-dimension 5-level; QOL: quality of life; VEINES-QOL: venous insufficiency epidemiological and economic study quality of life The clinical evaluation of the patient's status includes the clinical-etiologic-anatomic-pathophysiologic (CEAP) classification of chronic venous disease and the PTS scale using Villalta score. Health-related quality of life is evaluated using the generic questionnaire EQ-5D-5L, QOL and the disease-specific VEINES/QOL scores. The venous flow, compressibility, and insufficiency will be evaluated by DUS. Venous flow can be categorized as spontaneous, forced (when peripheral compression is applied), or absent. To assess insufficiency, the patient is examined while standing, and reflux is identified as a reversal of the velocity curve that lasts for more than 0.5 seconds following distal pneumatic decompression. Sample Size Determination According to the results of previous studies and literature review, the sample size is calculated based on the incidence of PTS evaluated by Villalta score. Assuming that the incidence of PTS in the test group is 16.7% and 38.2% in the control group, at the α level of 0.05 and the power of 0.8, 64 patients will be included in each group calculated by PASS 15.0 software. Considering the 20% abscission rate, 80 participants will be included in each group. Finally, 160 patients will be included in the study. Statistical analysis Continuous data will be presented as means and standard deviation (SD) if normally distributed, while categorical data will be presented as numbers and percentages. Dichotomous variables between groups will be compared by a two-sided chi-square test or Fisher’s exact test, and continuous variables will be compared using a two-sided t-test. Univariate and multivariate analyses will be performed by logistic regression analysis. P-value < 0.05 is considered to be statistically significant. Statistical analysis will be performed with SPSS, version 21.0. 3. Discussion Patients with an extensive thrombus burden, which extends from the iliofemoral to the distal popliteal or tibial veins, are at a higher risk of developing phlegmasia compared to those with proximal iliofemoral DVT. This risk is due to insufficient collateral venous drainage, particularly at the important confluence of veins at both the popliteal and common femoral zones. A larger thrombus burden is associated with a more severe clinical presentation and a greater propensity for PTS. 23 PMT may be more effective for rapidly restoring vein patency, quality of life, and clinical scores. However, the recently published and the largest Acute Venous Thrombolysis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial did not validate these improvements. In the ATTRACT study, there was no difference in PTS incidence or QOL at 2 years between those randomized to PMT plus anticoagulation and those receiving anticoagulation alone. Furthermore, PMT led to statistically significantly more major bleeding compared to the anticoagulation group (1.7% vs. 0.3%, p = 0.049%). 14 The ATTRACT trial failed to identify the benefits of PMT, possibly due to the inclusion of femoropopliteal DVT along with the more extensive iliofemoral DVTs, which may have diluted the potential outcomes. However, it is worth noting that in patients with extensive DVT, positive endovascular treatment can yield greater benefits compared to those with femoropopliteal disease alone. This observation is supported by the subgroup analysis of the Attract study conducted by Comerota et al. 15 The study demonstrated that PMT significantly reduced early leg symptoms in patients with acute iliofemoral deep vein thrombosis. Over a 24-month period, it also reduced PTS severity scores, decreased the proportion of patients who developed moderate or severe PTS, and resulted in greater improvement in venous disease-specific QOL. Furthermore, according to the guidelines for the choice of initial PMT technique in the Attract study, for subjects with poor popliteal vein inflow, physicians were required to use “infusion-first PMT” for subjects with poor popliteal vein inflow. This technique started with rt-PA infusion through a multi-side hole catheter for ≤ 30 hours. However, there was no stratified data available for the number of patients who underwent initial CDT due to occluded PV, which could prolong the duration of intervention and increase the risk of bleeding complications caused by more doses of thrombolytic drugs. Based on the reasons mentioned above, we therefore hypothesize that the advantages of PMT will be more significant if we limit the enrollment of patients to those with proximal DVT. Additionally, for individuals with femoropopliteal DVT that extends to the iliofemoral zone, rapid thrombus removal in a single procedure session using a modified approach could further reduce the incidence of CDT and preserve the function of the venous valve. It is crucial to understand the impact of inflow DVT on the outcome of PMT in extensive DVT. To our knowledge, the Reformation study is the first randomized controlled trial that has been implemented to evaluate the clinical effectiveness of removing inflow DVT in a single stage during the endovascular treatment of patients with extensive acute DVT. Due to the COVID-19 pandemic, the trial was delayed for one year. Currently, 21 patients have been recruited in this study, and 9 hospitals have participated. With the current study, it is possible to achieve the necessary number of patients (n = 160) within a reasonable timeframe. Based on the analysis of previous studies, our primary outcome is to measure the proportion of patients who develop PTS in a 2-year period. We will also evaluate the patency rate after treatment, Villalta score for diagnosing PTS, and CEAP classification for clinical situations as secondary outcomes. Additionally, we will use EQ-5D-5L, QOL and VEINES-QOL score to measure the general and disease-specific health-related quality of life. To reduce the potential for bias in an open-label study design, the evaluating physician will be blinded to the patient's history and treatment allocation during the end-point assessment. Additionally, all patients will be explicitly instructed not to disclose their treatment allocation while they are hospitalized. 4. Conclusion In conclusion, the Reformation study is the first RCT that aims to determine the long-term clinical impact of inflow DVT burden on the clinical efficacy of PMT in patients with extensive DVT. The results of this study will be valuable for determining the appropriate treatment for patients with extensive DVT. Declarations Ethical Approval: The Reformation study has been registered at www.clinicaltrials.gov (registration number: NCT05286710). The study protocol has been approved by the Institutional review board and Human Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (Approved number: KY2021-067-A). Funding: None Author Contribution Study design: Qihong Ni, Xiande Ye and Meng Ye; Data collection: Chunshui He, Hui Zhao and Wensheng Lou; Data analysis: Hui Zhuang and Hongfei Sang; Writing: Qihong Ni and Meng Ye. All authors reviewed the manuscript. Acknowledgements: None Conflict of interest: All authors declare no conflicts of interest. Availability of data and materials: Not applicable References Ortel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, Hutten BA, Jaff MR, Manja V, Schulman S, Thurston C, Vedantham S, Verhamme P, Witt DM, Florez D, Izcovich I, Nieuwlaat A, Ross R, Schünemann SJ, Wiercioch H, Zhang W, Zhang Y. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693–738. Spencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, Becker RC, Goldberg RJ. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006;21(7):722–7. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation. 2017;135(10):e146–603. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, Gutnikov SA, Edwards P, Mant D, Sackley CM, Farmer A, Sandercock PA, Dennis MS, Warlow CP, Bamford JM, Anslow P. Oxford Vascular Study. Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet. 2004;363(9425):1925–33. Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA. Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985–2009). Am J Med. 2014;127(9):829–e395. Baldwin MJ, Moore HM, Rudarakanchana N, Gohel M, Davies AH. Post-thrombotic syndrome: a clinical review. J Thromb Haemost. 2013;11(5):795–805. Kahn SR. The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 413-8. Renner E, Barnes GD. Antithrombotic Management of Venous Thromboembolism: JACC Focus Seminar. J Am Coll Cardiol. 2020;76(18):2142–54. Kahn SR, Shbaklo H, Lamping DL, Holcroft CA, Shrier I, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, Solymoss S, Desjardins L, Johri M, Ginsberg JS. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6(7):1105–12. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315–52. Kakkos SK, Gohel M, Baekgaard N, Bauersachs R, Bellmunt-Montoya S, Black SA, Ten Cate-Hoek AJ, Elalamy I, Enzmann FK, Geroulakos G, Gottsäter A, Hunt BJ, Mansilha A, Nicolaides AN, Sandset PM, Stansby G, Esvs G, de Committee GJ, Bastos Gonçalves F, Chakfé N, Hinchliffe R, Kolh P, Koncar I, Lindholt JS, Tulamo R, Twine CP, Vermassen F, Wanhainen A, De Document Reviewers MG, Comerota AJ, Gloviczki P, Kruip MJHA, Monreal M, Prandoni P. Vega de Ceniga M. Editor's Choice - European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg. 2021;61(1):9–82. Meissner MH, Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL, Lohr JM, McLafferty RB, Murad MH, Padberg F, Pappas P, Raffetto JD, Wakefield TW, Society for Vascular Surgery; American Venous Forum. Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2012;55(5):1449–62. Enden T, Haig Y, Kløw NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LO, Njaastad AM, Sandbæk G, Sandset PM, CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012;379(9810):31–8. Vedantham S, Goldhaber SZ, Julian JA, Kahn SR, Jaff MR, Cohen DJ, Magnuson E, Razavi MK, Comerota AJ, Gornik HL, Murphy TP, Lewis L, Duncan JR, Nieters P, Derfler MC, Filion M, Gu CS, Kee S, Schneider J, Saad N, Blinder M, Moll S, Sacks D, Lin J, Rundback J, Garcia M, Razdan R, VanderWoude E, Marques V, Kearon C. ATTRACT Trial Investigators. Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. N Engl J Med. 2017;377(23):2240–52. Comerota AJ, Kearon C, Gu CS, Julian JA, Goldhaber SZ, Kahn SR, Jaff MR, Razavi MK, Kindzelski AL, Bashir R, Patel P, Sharafuddin M, Sichlau MJ, Saad WE, Assi Z, Hofmann LV, Kennedy M, Vedantham S. ATTRACT Trial Investigators. Endovascular Thrombus Removal for Acute Iliofemoral Deep Vein Thrombosis. Circulation. 2019;139(9):1162–73. Engelberger RP, Spirk D, Willenberg T, Alatri A, Do DD, Baumgartner I, Kucher N. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis. Circ Cardiovasc Interv. 2015;8(1):e002027. Lichtenberg MKW, Stahlhoff S, Młyńczak K, Golicki D, Gagne P, Razavi MK, de Graaf R, Kolluri R, Kolasa K. Endovascular mechanical thrombectomy versus thrombolysis in patients with iliofemoral deep vein thrombosis - a systematic review and meta-analysis. Vasa. 2021;50(1):59–67. O'Connor P, Lookstein R. Endovascular Interventions for Venous Disease. Tech Vasc Interv Radiol. 2018;21(2):55–64. Drasler WJ, Jenson ML, Wilson GJ, Thielen JM, Protonotarios EI, Dutcher RG, Possis ZC. Rheolytic catheter for percutaneous removal of thrombus. Radiology. 1992;182(1):263–7. Ni Q, Long J, Guo X, Yang S, Meng X, Zhang L, Fang X, Ye M. Clinical efficacy of one-stage thrombus removal via contralateral femoral and ipsilateral tibial venous access for pharmacomechanical thrombectomy in entire-limb acute deep vein thrombosis. J Vasc Surg Venous Lymphat Disord. 2021;9(5):1128–35. Jeyabalan G, Marone L, Rhee R, Hirsch S, Makaroun MS, Cho J, Chaer RA. Inflow thrombosis does not adversely affect thrombolysis outcomes of symptomatic iliofemoral deep vein thrombosis. J Vasc Surg. 2011;54(2):448–53. Garcia MJ, Lookstein R, Malhotra R, Amin A, Blitz LR, Leung DA, Simoni EJ, Soukas PA. Endovascular Management of Deep Vein Thrombosis with Rheolytic Thrombectomy: Final Report of the Prospective Multicenter PEARL (Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths) Registry. J Vasc Interv Radiol. 2015;26(6):777–85. quiz 786. Cooley BC, Chen CY, Hess R, Schmeling G. Incomplete resolution of deep vein thrombosis under reduced flow conditions. Thromb Res. 2013;131:55–8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4157062","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":284343833,"identity":"d5e0a143-1c66-4639-bbe7-b82177fb2e84","order_by":0,"name":"Qihong Ni","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qihong","middleName":"","lastName":"Ni","suffix":""},{"id":284343836,"identity":"3286a67a-f27a-4e07-b851-591054e833c1","order_by":1,"name":"Xiande Ye","email":"","orcid":"","institution":"Shanghai Pudong New Area People’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiande","middleName":"","lastName":"Ye","suffix":""},{"id":284343838,"identity":"d0be3e9b-0205-4204-8a31-1290113dc546","order_by":2,"name":"Chunshui He","email":"","orcid":"","institution":"Hospital of Chengdu University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chunshui","middleName":"","lastName":"He","suffix":""},{"id":284343840,"identity":"f9b9b07b-973a-4b75-8fc8-7efff0fd41ca","order_by":3,"name":"Hui Zhao","email":"","orcid":"","institution":"Affiliated Hospital of Nantong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zhao","suffix":""},{"id":284343842,"identity":"14791bfc-5e94-4347-b82e-425e36c7ed8a","order_by":4,"name":"Wensheng Lou","email":"","orcid":"","institution":"Nanjing Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wensheng","middleName":"","lastName":"Lou","suffix":""},{"id":284343844,"identity":"d183fdb3-8841-4bef-a798-6f360c524614","order_by":5,"name":"Hui Zhuang","email":"","orcid":"","institution":"Xiamen University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zhuang","suffix":""},{"id":284343846,"identity":"7080a4fc-8764-472e-b88b-7825e20b349f","order_by":6,"name":"Hongfei Sang","email":"","orcid":"","institution":"The Second Affiliated Hospital of Soochow University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hongfei","middleName":"","lastName":"Sang","suffix":""},{"id":284343849,"identity":"9419790d-9fcc-4e8f-94b2-67f2ec0e00c9","order_by":7,"name":"Ziheng Wu","email":"","orcid":"","institution":"Zhejiang University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ziheng","middleName":"","lastName":"Wu","suffix":""},{"id":284343854,"identity":"cb40488a-09e5-40b3-87b9-aee0101b9824","order_by":8,"name":"Meng Ye","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIiWNgGAWjYDCCAyi8CgkefvbGxocf8GthbEDwztjISPYcbjaWIFoLY1uajcGN9DYBHjw6+I43P3/wcQ9DYr/Y4WMPv7Ad5pGc+bCNQYLBTk63AbsWyTPHDBtnPGNInDk7Ld1YhucwD790YtuDAoZkY7MD2LUY3MhhbOY5wJC44XaOmbSEBNCW2YntBhIMBxK3EdKy/3b+N2kJg8M8BjcPtknwEKNlg3QOm+SHhDQegxuM+LWA/DJzxgEG4xm308ykGQ7Y8Ej2JAID2QC3X4Ah9uDDhwMMsv2zk59J/vwnYc/Pfvzhww8VdnK4tEDBf8cGIMmMiA4DvMrBwB5EMP4grHAUjIJRMApGIAAAngFk301FxuAAAAAASUVORK5CYII=","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Meng","middleName":"","lastName":"Ye","suffix":""}],"badges":[],"createdAt":"2024-03-24 08:29:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4157062/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4157062/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53757628,"identity":"4d29efda-24d2-40f3-9052-606507736c9a","added_by":"auto","created_at":"2024-03-29 19:08:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":22004,"visible":true,"origin":"","legend":"\u003cp\u003ePatients flow diagram.\u003c/p\u003e\n\u003cp\u003eDVT: Deep vein thrombosis; PMT: Pharmacomechanical thrombectomy.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4157062/v1/0e480c8707f230a9efb77dbe.png"},{"id":54483404,"identity":"6f1c64b6-b9eb-48de-98ff-7f628c5686a8","added_by":"auto","created_at":"2024-04-11 08:42:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":464681,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4157062/v1/06308682-c32a-4794-938d-f557fd1f2174.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Protocol of the Reformation study: a prospective, multicenter, randomized controlled trial on the improvement of rheolytic thrombectomy for acute deep vein thrombosis of the whole lower limb by primary popliteal vein thrombosis clearance","fulltext":[{"header":"Strengths and limitations of this study","content":"\u003cp\u003e1) To our knowledge,\u0026nbsp;the Reformation study is the first randomized controlled trial to determine whether inflow DVT burden affects the clinical efficacy of PMT in patients with extensive DVT over the long term.\u003c/p\u003e\n\u003cp\u003e2) This study will provide high-quality evidence for the clinical application of PMT in the treatment of extensive DVT.\u003c/p\u003e\n\u003cp\u003e3) This study is an evaluator-blind trial. The participants and surgeons cannot be blinded.\u003c/p\u003e\n\u003cp\u003e4) The 24-month follow-up period is relatively not long enough for evaluating incidence of PTS in DVT patients.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eVenous thromboembolism (VTE) includes deep vein thrombosis (DVT) and pulmonary embolism (PE).\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e VTE is the third most common cardiovascular disease after myocardial infarction and stroke.\u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Up to 50% of the patients suffering from DVT will develop post-thrombotic syndrome (PTS), which may be accompanied by major disability.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The pathophysiologic mechanism of PTS involves the development of venous hypertension and venous valve incompetence. Following DVT, serious PTS, including venous ulcers, develops in up to 10% of patients.\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe standard strategy for preventing further clot formation and recurrent PE is systemic anticoagulation.\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e However, this method cannot eliminate existing thrombus, which can result in PTS and venous valvular insufficiency. In contrast, catheter-directed thrombolysis (CDT) directly infuses thrombolytic agents into the occluded vein, reducing systemic drug exposure and the necessary therapeutic dose. Current evidence supports the utility of endovascular methods, such as CDT, which may be useful for patients who have severe symptoms, extensive DVT, high physiologic reserve and long-life expectancy, low bleeding risk, and who do not respond well to initial oral anticoagulation therapy, particularly within the acute time frame of 2\u0026ndash;4 weeks after symptom onset.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Although there are certain benefits associated with CDT, recent trials such as ATTRACT and CAVA have not been able to confirm them. Moreover, CDT has a relatively longer infusion time, ranging from 8 to 87 hours, which increases the risk of major bleeding during the procedure.\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePercutaneous mechanical thrombectomy (PMT) is an alternative method to remove acute DVT.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e.\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e The AngioJet rheolytic thrombectomy system is one of the most widely used PMT catheters.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e The system uses high-pressure saline or thrombolytic agent jets to create a pressure gradient based on the Bernoulli effect, which fragments and aspirates the thrombus. Previous comparative case series studies show that PMT has demonstrated potential benefits compared to CDT alone, including lower doses of thrombolytic agents and shorter infusion times. This results in a reduced risk of hemorrhagic events and, in turn, less use of hospital resources.\u003c/p\u003e \u003cp\u003eMoreover, owing to newly modified approaches, it is now possible to eliminate DVT in all segments simultaneously. Our previous study demonstrated that using a contra-lateral femoral vein or tibial vein for one-stage inflow DVT removal resulted in a significantly higher rate of thrombus clearance in a single session compared to the traditional ipsilateral popliteal venous approach.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Furthermore, patients who required further CDT and PTS treatment at the 2-year follow-up were significantly lower in the modified access group. However, a study conducted by Jeyabalan G et al. revealed that inflow thrombosis did not affect the outcomes of thrombolysis in patients with popliteal and tibial clots who underwent PMT from thrombosed PV access. After treatment, 90% of the patients regained patency of the popliteal vein, but more than 60% of the patients needed additional treatment after PMT.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIt is uncertain whether removing inflow venous thrombus from the tibial and distal popliteal areas would improve venous drainage, maintain patency, and reduce venous reflux. Although these results are promising, there is still no conclusive evidence from multicenter randomized controlled trials (RCTs) to support them. Therefore, we have initiated the Reformation study to address this controversy by improving rheolytic thrombectomy for acute deep vein thrombosis of the lower limb through primary popliteal vein thrombosis clearance.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy objective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary study objective is to determine whether removing blood clots in the distal popliteal vein using a modified approach can reduce the incidence of PTS over a 24-month follow-up period in patients with extensive acute DVT involving the iliac and femoropopliteal veins when compared to performing PMT through the traditional approach of the ipsilateral popliteal vein. Secondary objectives include: (a) Patency rate immediately after lonely mechanical thrombectomy. (b) Total time of interventional surgery (Including duration of subsequent catheter-directed thrombolysis). (c) Total dosage of urokinase used for the procedure. (d) Patency rate of lower limb vein at post-interventional 12 and 24 months. (e) Deep venous valve function evaluation by ultrasound at post-interventional 12 and 24 months. (f) Quality of life (QOL) score, venous insufficiency epidemiological and economic study quality of life (VEINES-QOL) score, and European quality of life 5-dimension 5-level (EQ-5D-5L) score at post-interventional 3, 6, 12 and 24 months. (g) Re-intervention rate within 24 months after operation. (h) Treatment rate of catheter-directed thrombolysis after mechanical thrombectomy.\u003c/p\u003e\n\u003cp\u003eThe safety outcomes include procedural complications such as hematoma at the puncture site, hemoglobinuria or hemolytic jaundice, bleeding events, and all-cause death during the follow-up period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReformation is an ongoing, multicenter, randomized, open-label, two-arm controlled trial sponsored by Boston Scientific. The study design, execution, and data analysis are independent of the sponsor. 160 patients will be recruited from and randomized at 9 participating hospitals in China. The first patient was recruited in October 2022. The study protocol has been approved by the Institutional review board and Human Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (Approved number: KY2021-067-A). All participants will provide written informed consent before enrollment. Patients will be randomly allocated in a 1:1 ratio by central stratification and block randomization method to receive either modified or traditional PMT treatment. The patients flow diagram was shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The statistical analyst of this study generates the random allocation table through SAS software. The block length and random allocation table of each center will be kept blind and not be opened during the whole study period. The study was overseen by an independent Data Safety Monitoring Board and was conducted in accordance with Good Clinical Practices.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo be eligible for inclusion, patients must be between 18\u0026ndash;75 years old and have a first-time symptomatic DVT involving the iliac and femoropopliteal vein, verified by compression ultrasonography or venography. The study aims to recruit a total of 160 individuals with entire-limb acute DVT. Out of these, 80 participants will be treated with PMT via the contralateral femoral vein, jugular vein or ipsilateral tibial vein, which is referred to as the modified access group. The remaining 80 participants will be treated with PMT via the ipsilateral popliteal vein, which is referred to as the traditional access group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion Criteria (\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e:\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eInclusion criteria\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWe include the patients with all the following criteria:\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1) Age between 18\u0026ndash;75 years old\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2) Acute DVT occurred less than 14 days from the onset of the disease\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3) DVT with thrombosis involving the iliac vein, common femoral vein, distal popliteal vein, and/or calf vein\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4) The patient must have signed an informed consent form\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"1\"\u003eDVT: deep vein thrombosis\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e1) Age between 18\u0026ndash;75 years old;\u003c/p\u003e\n\u003cp\u003e2) Acute DVT occurred less than 14 days from the onset of the disease;\u003c/p\u003e\n\u003cp\u003e3) DVT with thrombosis involving the iliac vein, common femoral vein, distal popliteal vein, and/or calf vein;\u003c/p\u003e\n\u003cp\u003e4) The patient must have signed an informed consent form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria (\u003c/strong\u003eTable\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e:\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eExclusion criteria\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWe exclude the patients with either of the following criteria:\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1) Patients with a history of DVT in the same lower limb\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2) Plasma Creatinine level greater than 180umol/L\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3) Patients who are contraindicated for thrombolysis treatment\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4) Patients with thrombosis in inferior vena cava\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5) Patients who have a known allergy to heparin, low molecular weight heparin, or contrast agent\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6) Patients who have participated in a clinical trial within the past three months\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7) Women who are pregnant or lactation\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8) Patients with other diseases that may interfere with the study or significantly reduce their life expectancy (less than 2 years)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9) Patients with autoimmune thrombopathy\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10) Patients who are unwilling or unable to participate in the study\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"1\"\u003eDVT: deep vein thrombosis\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e1) Patients with a history of DVT in the same lower limb;\u003c/p\u003e\n\u003cp\u003e2) Plasma Creatinine level greater than 180umol/L;\u003c/p\u003e\n\u003cp\u003e3) Patients who are contraindicated for thrombolysis treatment;\u003c/p\u003e\n\u003cp\u003e4) Patients with thrombosis in inferior vena cava;\u003c/p\u003e\n\u003cp\u003e5) Patients who have a known allergy to heparin, low molecular weight heparin, or contrast agent;\u003c/p\u003e\n\u003cp\u003e6) Patients who have participated in a clinical trial within the past three months;\u003c/p\u003e\n\u003cp\u003e7) Women who are pregnant or lactation;\u003c/p\u003e\n\u003cp\u003e8) Patients with other diseases that may interfere with the study or significantly reduce their life expectancy (less than 2 years);\u003c/p\u003e\n\u003cp\u003e9) Patients with autoimmune thrombopathy;\u003c/p\u003e\n\u003cp\u003e10) Patients who are unwilling or unable to participate in the study;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConduct of the study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients who meet the inclusion criteria and do not have any exclusion criteria will be invited to participate in this study. Once they provide written informed consent, they will be assigned randomly assigned to receive PMT treatment through either modified or traditional access. Anticoagulation will begin with full therapeutic anticoagulation with twice-daily weight-based low molecular weight heparin (LMWH) for at least 8 hours, followed by oral anticoagulation therapy for at least 6 months. The oral anticoagulation therapy will be administered through new oral anticoagulants or warfarin (maintaining INR between 2 and 3). Compression stockings, class II, will also be used as a standard adjunctive treatment, daily for 24 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePMT procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll endovascular treatments will be done using local anesthesia. Pre-procedure and post-procedure venography from a dorsal foot vein will be conducted to assign a thrombus score to each of the six venous segments (Common iliac, external iliac, common femoral, central femoral, peripheral femoral, and popliteal veins) according to the following criteria: complete occlusion of the venous segment was given a score of 3, substantial occlusion (50\u0026ndash;99%) of the venous segment was given a score of 2, partial occlusion (0\u0026ndash;50%) of the venous segment was given a score of 1, and a patent venous segment was given a score of 0. Thrombus scores were totaled for each enrolled patient with the potential range of 0 to 18. The degree of thrombus removal was graded by calculating the percentage reduction in the patient's total thrombus score.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eDuring the PMT procedure, it is recommended to use a retrievable IVC filter that should be removed 14\u0026ndash;21 days after treatment. To establish venous access, ultrasound or venography guidance will be used. For the modified approach, the decision to use contralateral femoral vein, jugular vein or ipsilateral tibial vein access will be at the discretion of the operating interventionist. For the traditional approach, the ipsilateral popliteal venous access will be obtained. Pulse spray thrombolysis using the 6F Angiojet device will initially be employed to treat the occluded veins, with a maximum of 250,000 UI Urokinase administered. After a 15-minute dwell time, the Angiojet catheter will be used to eliminate residual thrombus, by employing the standard mechanical aspiration thrombectomy technique. CDT will be used selectively as needed for residual thrombus, using a multiple-side hole catheter (Angiodynamic, USA), with the maximum allowable CDT duration being 72 hours. During the CDT procedure, hemostasis will be monitored by analyzing hemoglobin, fibrinogen, D-dimer, INR, and platelet counts 3 times a day. The dose of urokinase will be adjusted according to the result of fibrinogen. The effect of treatment will be assessed daily by venography, and Percutaneous balloon angioplasty (PTA) will be performed if the stenosis of the iliac vein diameter is greater than 50%. A stent will be placed if the residual stenosis exceeds 50% after PTA treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter their intervention, Patients will have follow-up at scheduled 14\u0026thinsp;\u0026plusmn;\u0026thinsp;7 days, 12 months, and 24 months after their intervention. At 14\u0026thinsp;\u0026plusmn;\u0026thinsp;7day follow-up, venography will be conducted to evaluate the technical success rate during their return for IV filter removal. At each visit, physicians who are not familiar with the patient's history will conduct a clinical evaluation and a duplex ultrasound (DUS) assessment of the affected lower limb. Additionally, a telephone interview will be conducted 3, 6, and 18 months after the intervention. (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eEnrollment, intervention and follow-up schedule\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eEnrollment\u003c/p\u003e\n\u003cp\u003e(Day \u0026minus;\u0026thinsp;1)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAllocation\u003c/p\u003e\n\u003cp\u003e(Day 0)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFollow-up\u003c/p\u003e\n\u003cp\u003e(14 days)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFollow-up\u003c/p\u003e\n\u003cp\u003e3 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFollow-up\u003c/p\u003e\n\u003cp\u003e6 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFollow-up\u003c/p\u003e\n\u003cp\u003e12 months\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eFollow-up\u003c/p\u003e\n\u003cp\u003e24 months\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEligibility screen\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInformed consent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAllocation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVenography\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eClinical evaluation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCEAP classification\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePTS scale by Villalta score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDuplex ultrasound assessment\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVenous patency\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDeep venous valve function\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEQ-5D-5L score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eQOL score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eVEINES/QOL score\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026times;\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eCEAP: clinical-etiologic-anatomic-pathophysiologic; PTS: post-thrombotic syndrome; EQ-5D-5L: European quality of life 5-dimension 5-level;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eQOL: quality of life; VEINES-QOL: venous insufficiency epidemiological and economic study quality of life\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eThe clinical evaluation of the patient's status includes the clinical-etiologic-anatomic-pathophysiologic (CEAP) classification of chronic venous disease and the PTS scale using Villalta score. Health-related quality of life is evaluated using the generic questionnaire EQ-5D-5L, QOL and the disease-specific VEINES/QOL scores.\u003c/p\u003e\n\u003cp\u003eThe venous flow, compressibility, and insufficiency will be evaluated by DUS. Venous flow can be categorized as spontaneous, forced (when peripheral compression is applied), or absent. To assess insufficiency, the patient is examined while standing, and reflux is identified as a reversal of the velocity curve that lasts for more than 0.5 seconds following distal pneumatic decompression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size Determination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the results of previous studies and literature review, the sample size is calculated based on the incidence of PTS evaluated by Villalta score. Assuming that the incidence of PTS in the test group is 16.7% and 38.2% in the control group, at the \u0026alpha; level of 0.05 and the power of 0.8, 64 patients will be included in each group calculated by PASS 15.0 software. Considering the 20% abscission rate, 80 participants will be included in each group. Finally, 160 patients will be included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous data will be presented as means and standard deviation (SD) if normally distributed, while categorical data will be presented as numbers and percentages. Dichotomous variables between groups will be compared by a two-sided chi-square test or Fisher\u0026rsquo;s exact test, and continuous variables will be compared using a two-sided t-test. Univariate and multivariate analyses will be performed by logistic regression analysis. P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 is considered to be statistically significant. Statistical analysis will be performed with SPSS, version 21.0.\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003ePatients with an extensive thrombus burden, which extends from the iliofemoral to the distal popliteal or tibial veins, are at a higher risk of developing phlegmasia compared to those with proximal iliofemoral DVT. This risk is due to insufficient collateral venous drainage, particularly at the important confluence of veins at both the popliteal and common femoral zones. A larger thrombus burden is associated with a more severe clinical presentation and a greater propensity for PTS.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e PMT may be more effective for rapidly restoring vein patency, quality of life, and clinical scores. However, the recently published and the largest Acute Venous Thrombolysis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial did not validate these improvements. In the ATTRACT study, there was no difference in PTS incidence or QOL at 2 years between those randomized to PMT plus anticoagulation and those receiving anticoagulation alone. Furthermore, PMT led to statistically significantly more major bleeding compared to the anticoagulation group (1.7% vs. 0.3%, p\u0026thinsp;=\u0026thinsp;0.049%).\u003csup\u003e14\u003c/sup\u003e The ATTRACT trial failed to identify the benefits of PMT, possibly due to the inclusion of femoropopliteal DVT along with the more extensive iliofemoral DVTs, which may have diluted the potential outcomes. However, it is worth noting that in patients with extensive DVT, positive endovascular treatment can yield greater benefits compared to those with femoropopliteal disease alone. This observation is supported by the subgroup analysis of the Attract study conducted by Comerota et al.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e The study demonstrated that PMT significantly reduced early leg symptoms in patients with acute iliofemoral deep vein thrombosis. Over a 24-month period, it also reduced PTS severity scores, decreased the proportion of patients who developed moderate or severe PTS, and resulted in greater improvement in venous disease-specific QOL. Furthermore, according to the guidelines for the choice of initial PMT technique in the Attract study, for subjects with poor popliteal vein inflow, physicians were required to use \u0026ldquo;infusion-first PMT\u0026rdquo; for subjects with poor popliteal vein inflow. This technique started with rt-PA infusion through a multi-side hole catheter for \u0026le;\u0026thinsp;30 hours. However, there was no stratified data available for the number of patients who underwent initial CDT due to occluded PV, which could prolong the duration of intervention and increase the risk of bleeding complications caused by more doses of thrombolytic drugs.\u003c/p\u003e \u003cp\u003eBased on the reasons mentioned above, we therefore hypothesize that the advantages of PMT will be more significant if we limit the enrollment of patients to those with proximal DVT. Additionally, for individuals with femoropopliteal DVT that extends to the iliofemoral zone, rapid thrombus removal in a single procedure session using a modified approach could further reduce the incidence of CDT and preserve the function of the venous valve.\u003c/p\u003e \u003cp\u003eIt is crucial to understand the impact of inflow DVT on the outcome of PMT in extensive DVT. To our knowledge, the Reformation study is the first randomized controlled trial that has been implemented to evaluate the clinical effectiveness of removing inflow DVT in a single stage during the endovascular treatment of patients with extensive acute DVT. Due to the COVID-19 pandemic, the trial was delayed for one year. Currently, 21 patients have been recruited in this study, and 9 hospitals have participated. With the current study, it is possible to achieve the necessary number of patients (n\u0026thinsp;=\u0026thinsp;160) within a reasonable timeframe.\u003c/p\u003e \u003cp\u003eBased on the analysis of previous studies, our primary outcome is to measure the proportion of patients who develop PTS in a 2-year period. We will also evaluate the patency rate after treatment, Villalta score for diagnosing PTS, and CEAP classification for clinical situations as secondary outcomes. Additionally, we will use EQ-5D-5L, QOL and VEINES-QOL score to measure the general and disease-specific health-related quality of life. To reduce the potential for bias in an open-label study design, the evaluating physician will be blinded to the patient's history and treatment allocation during the end-point assessment. Additionally, all patients will be explicitly instructed not to disclose their treatment allocation while they are hospitalized.\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eIn conclusion, the Reformation study is the first RCT that aims to determine the long-term clinical impact of inflow DVT burden on the clinical efficacy of PMT in patients with extensive DVT. The results of this study will be valuable for determining the appropriate treatment for patients with extensive DVT.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthical Approval:\u003c/strong\u003e \u003cp\u003eThe Reformation study has been registered at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.clinicaltrials.gov\" target=\"_blank\"\u003ewww.clinicaltrials.gov\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (registration number: NCT05286710). The study protocol has been approved by the Institutional review board and Human Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (Approved number: KY2021-067-A).\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eStudy design: Qihong Ni, Xiande Ye and Meng Ye; Data collection: Chunshui He, Hui Zhao and Wensheng Lou; Data analysis: Hui Zhuang and Hongfei Sang; Writing: Qihong Ni and Meng Ye. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConflict of interest:\u003c/strong\u003e \u003cp\u003eAll authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOrtel TL, Neumann I, Ageno W, Beyth R, Clark NP, Cuker A, Hutten BA, Jaff MR, Manja V, Schulman S, Thurston C, Vedantham S, Verhamme P, Witt DM, Florez D, Izcovich I, Nieuwlaat A, Ross R, Sch\u0026uuml;nemann SJ, Wiercioch H, Zhang W, Zhang Y. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693\u0026ndash;738.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSpencer FA, Emery C, Lessard D, Anderson F, Emani S, Aragam J, Becker RC, Goldberg RJ. The Worcester Venous Thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006;21(7):722\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jim\u0026eacute;nez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation. 2017;135(10):e146\u0026ndash;603. American Heart Association Statistics Committee and Stroke Statistics Subcommittee.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, Gutnikov SA, Edwards P, Mant D, Sackley CM, Farmer A, Sandercock PA, Dennis MS, Warlow CP, Bamford JM, Anslow P. Oxford Vascular Study. Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet. 2004;363(9425):1925\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA. Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985\u0026ndash;2009). Am J Med. 2014;127(9):829\u0026ndash;e395.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaldwin MJ, Moore HM, Rudarakanchana N, Gohel M, Davies AH. Post-thrombotic syndrome: a clinical review. J Thromb Haemost. 2013;11(5):795\u0026ndash;805.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKahn SR. The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Program. 2016; 2016(1): 413-8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRenner E, Barnes GD. Antithrombotic Management of Venous Thromboembolism: JACC Focus Seminar. J Am Coll Cardiol. 2020;76(18):2142\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKahn SR, Shbaklo H, Lamping DL, Holcroft CA, Shrier I, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, Solymoss S, Desjardins L, Johri M, Ginsberg JS. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6(7):1105\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKakkos SK, Gohel M, Baekgaard N, Bauersachs R, Bellmunt-Montoya S, Black SA, Ten Cate-Hoek AJ, Elalamy I, Enzmann FK, Geroulakos G, Gotts\u0026auml;ter A, Hunt BJ, Mansilha A, Nicolaides AN, Sandset PM, Stansby G, Esvs G, de Committee GJ, Bastos Gon\u0026ccedil;alves F, Chakf\u0026eacute; N, Hinchliffe R, Kolh P, Koncar I, Lindholt JS, Tulamo R, Twine CP, Vermassen F, Wanhainen A, De Document Reviewers MG, Comerota AJ, Gloviczki P, Kruip MJHA, Monreal M, Prandoni P. Vega de Ceniga M. Editor's Choice - European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg. 2021;61(1):9\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeissner MH, Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL, Lohr JM, McLafferty RB, Murad MH, Padberg F, Pappas P, Raffetto JD, Wakefield TW, Society for Vascular Surgery; American Venous Forum. Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2012;55(5):1449\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnden T, Haig Y, Kl\u0026oslash;w NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LO, Njaastad AM, Sandb\u0026aelig;k G, Sandset PM, CaVenT Study Group. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012;379(9810):31\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVedantham S, Goldhaber SZ, Julian JA, Kahn SR, Jaff MR, Cohen DJ, Magnuson E, Razavi MK, Comerota AJ, Gornik HL, Murphy TP, Lewis L, Duncan JR, Nieters P, Derfler MC, Filion M, Gu CS, Kee S, Schneider J, Saad N, Blinder M, Moll S, Sacks D, Lin J, Rundback J, Garcia M, Razdan R, VanderWoude E, Marques V, Kearon C. ATTRACT Trial Investigators. Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. N Engl J Med. 2017;377(23):2240\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eComerota AJ, Kearon C, Gu CS, Julian JA, Goldhaber SZ, Kahn SR, Jaff MR, Razavi MK, Kindzelski AL, Bashir R, Patel P, Sharafuddin M, Sichlau MJ, Saad WE, Assi Z, Hofmann LV, Kennedy M, Vedantham S. ATTRACT Trial Investigators. Endovascular Thrombus Removal for Acute Iliofemoral Deep Vein Thrombosis. Circulation. 2019;139(9):1162\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEngelberger RP, Spirk D, Willenberg T, Alatri A, Do DD, Baumgartner I, Kucher N. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis. Circ Cardiovasc Interv. 2015;8(1):e002027.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLichtenberg MKW, Stahlhoff S, Młyńczak K, Golicki D, Gagne P, Razavi MK, de Graaf R, Kolluri R, Kolasa K. Endovascular mechanical thrombectomy versus thrombolysis in patients with iliofemoral deep vein thrombosis - a systematic review and meta-analysis. Vasa. 2021;50(1):59\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Connor P, Lookstein R. Endovascular Interventions for Venous Disease. Tech Vasc Interv Radiol. 2018;21(2):55\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrasler WJ, Jenson ML, Wilson GJ, Thielen JM, Protonotarios EI, Dutcher RG, Possis ZC. Rheolytic catheter for percutaneous removal of thrombus. Radiology. 1992;182(1):263\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNi Q, Long J, Guo X, Yang S, Meng X, Zhang L, Fang X, Ye M. Clinical efficacy of one-stage thrombus removal via contralateral femoral and ipsilateral tibial venous access for pharmacomechanical thrombectomy in entire-limb acute deep vein thrombosis. J Vasc Surg Venous Lymphat Disord. 2021;9(5):1128\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeyabalan G, Marone L, Rhee R, Hirsch S, Makaroun MS, Cho J, Chaer RA. Inflow thrombosis does not adversely affect thrombolysis outcomes of symptomatic iliofemoral deep vein thrombosis. J Vasc Surg. 2011;54(2):448\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia MJ, Lookstein R, Malhotra R, Amin A, Blitz LR, Leung DA, Simoni EJ, Soukas PA. Endovascular Management of Deep Vein Thrombosis with Rheolytic Thrombectomy: Final Report of the Prospective Multicenter PEARL (Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths) Registry. J Vasc Interv Radiol. 2015;26(6):777\u0026ndash;85. quiz 786.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCooley BC, Chen CY, Hess R, Schmeling G. Incomplete resolution of deep vein thrombosis under reduced flow conditions. Thromb Res. 2013;131:55\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Randomized controlled trial, Deep vein thrombosis, Pharmacomechanical thrombectomy, Post-thrombotic syndrome","lastPublishedDoi":"10.21203/rs.3.rs-4157062/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4157062/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e: Pharmacomechanical thrombectomy (PMT) can be a useful treatment for restoring vein patency quickly especially for extensive acute deep vein thrombosis (DVT). However, previous evidence failed to validate the effectiveness of PMT in reducing the incidence of post-thrombotic syndrome (PTS). To address this controversy, the Reformation study aims to improve rheolytic thrombectomy for acute deep vein thrombosis of the lower limb through primary popliteal vein thrombosis clearance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod and analysis\u003c/strong\u003e: Reformation is a prospective randomized multicenter trial. It has 160 patients in two groups: the modified access group (80 patients) and the traditional access group (80 patients). The purpose of this study is to assess whether the modified access approach for removing inflow thrombus in a one-stage procedure is more effective in enhancing the success rate of the procedure and reducing the incidence of post-thrombotic syndrome during a 24-month follow-up period, for patients with acute whole limb DVT.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and dissemination\u003c/strong\u003e: The Reformation study has been registered at \u003ca href=\"http://www.clinicaltrials.gov\" target=\"_blank\"\u003ewww.clinicaltrials.gov\u003c/a\u003e (registration number: NCT05286710). The study protocol has been approved by the Institutional review board and Human Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiao Tong University (Approved number: KY2021-067-A). The results will be disseminated by publication in a peer-reviewed journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration number\u003c/strong\u003e: NCT05286710\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol version and date\u003c/strong\u003e: V.1.2, 20 August 2022\u003c/p\u003e","manuscriptTitle":"Protocol of the Reformation study: a prospective, multicenter, randomized controlled trial on the improvement of rheolytic thrombectomy for acute deep vein thrombosis of the whole lower limb by primary popliteal vein thrombosis clearance","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-29 19:08:40","doi":"10.21203/rs.3.rs-4157062/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"26848590-625a-48bb-a8fc-c3f1f8e61f6e","owner":[],"postedDate":"March 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-11T08:42:20+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-29 19:08:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4157062","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4157062","identity":"rs-4157062","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}