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
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
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.