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Keywords:

  • fibrinolytic therapy;
  • iliac vein;
  • May Thurner syndrome;
  • mechanical thrombectomy;
  • stents;
  • venous thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

Summary. Background: Optimal treatment for iliac vein thrombosis has not been established by randomized clinical trials largely owing to difficulty in patient recruitment. To assess the feasibility of a prospective randomized trial of thrombolysis and stenting, we determined the incidence of iliac vein thrombosis and randomization eligibility based on criteria for two ongoing trials. Methods: All patients with incident leg deep vein thrombosis during the calendar year 2005 seen at the Mayo Clinic were identified to determine the frequency of iliac vein involvement and the number undergoing endovascular therapies. Each patient was assessed for eligibility for potential randomization into a theoretic trial of thrombolytic therapy. Results: Ninety-five (of 394) patients had iliac vein involvement. Of these, only nine patients would have been suitable for randomization. Of the remaining 86 patients, prolonged symptom duration (n = 28), active cancer (n = 24) and advanced age (n = 19) were the most common exclusion criteria. Of 31 patients who had intervention, 75% had at least one contraindication for randomization. Conclusions: Despite a philosophy of aggressive treatment for iliac vein thrombosis at this institution, the number of cases that could potentially be randomized into a clinical trial is relatively small. Trial design may require either multicenter cooperation or exclusion criteria revision for adequate recruitment.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

Optimal treatment for iliac vein thrombosis has not been adequately established by randomized clinical trials. A number of small studies have suggested improved patency rates with reduced post-thrombotic sequelae in patients given endovascular treatment for their iliac vein thrombosis [1–8]. Although promising, these studies have been limited by either inadequate power or non-randomized trial design and therefore do not provide definitive proof of superiority compared with more conservative therapy [9]. For these reasons, recent guidelines suggesting a preference for mechanical thrombectomy and catheter-directed thrombolytic therapy for iliac vein thrombosis are supported by only a weak recommendation grade of either 2B or 2C [10,11]. Randomized controlled trials, including the CavenT and ATTRACT trials, are in varying stages of patient recruitment to address these limitations [12,13]. Both trials have included femoral vein thrombosis as a potential indication for study participation. The CavenT trial has recently reached its goal of enrollment of 200 participants.

Prior randomized trials have been limited by inadequate patient recruitment and insufficient power to detect statistically significant treatment differences [1]. This limitation may be overcome by either increasing the number of participating centers or relaxing the recruitment restriction in order to increase study participation. Both approaches have notable disadvantages. Increased center participation reduces uniformity of patient assessment and procedural process. Moreover, multicenter recruitment may be adversely affected by inadequate operator expertise. For these reasons, increasing study participation at each center and limiting the number of centers involved may be preferable, particularly for a technique with such operator dependence. The stringency of inclusion and exclusion criteria of ongoing trials, however, reduces the feasibility of such an approach. Furthermore, current eligibility criteria may fail to recapitulate actual clinical practise.

To assess the feasibility of a prospective randomized trial of thrombolysis and stenting for iliac venous thrombosis, we determined the incidence of iliac vein thrombosis and eligibility for thrombolytic therapy based on published criteria from two large ongoing randomized trials. All patients with the diagnosis of lower extremity deep vein thrombosis (DVT) during the calendar year 2005 were identified to determine the percentage with iliac involvement and the number receiving endovascular therapies. Exclusion criteria for potential randomization into a theoretic trial of thrombolytic therapy were defined for each patient. To determine the applicability of these trial results to clinical practise, randomization criteria were also assessed for patients undergoing and not undergoing an endovascular treatment at this institution.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

Study population, design and setting

To determine the frequency of iliac vein thrombosis relative to deep vein thrombosis at other locations, all patients with incident lower extremity DVT who underwent evaluation at the Mayo Clinic from 1 January 2005 through to 31 December 2005 were included. The radiographic data for each patient were then carefully scrutinized to identify a cohort of patients with iliac vein involvement. Iliac vein thrombosis was defined as thrombosis involving the venous segments from the inferior vena caval bifurcation up to the common femoral venous bifurcation. In contrast to the ATTRACT and CavenT trials, patients with isolated femoral vein thrombosis were not included as part of this definition.

The diagnosis of DVT was confirmed by ultrasound imaging, computed tomography, venography or magnetic resonance imaging. The ultrasound protocol for DVT assessment included color Doppler and grey scale assessment with and without compression of the common femoral, deep femoral, femoral, popliteal, posterior tibial, peroneal and great saphenous veins. Spectral Doppler was performed at the common femoral vein and saphenofemoral junction with and without valsalva to assess patency of more cephalad venous segments. The mid femoral vein and popliteal vein were also assessed by spectral Doppler. When identified, the most proximal extent of each thrombus was documented. In the absence of femoral vein thrombosis, iliac venous segments were not specifically assessed unless requested by the referring physician or if there were spectral Doppler findings suggestive of a more proximal stenosis or occlusion.

Data were collected from the Mayo Clinic electronic medical record-keeping system, which contains the details of every inpatient hospitalization, every outpatient visit regardless of the provider, every radiology examination and all laboratory and pathology results (including autopsy reports), death certificates and relevant correspondence. Comprehensive thrombophilia testing available at the time of clinical presentation to the Mayo Clinic was performed when appropriate. The study was approved by the Mayo Clinic Institutional Review Board.

To determine the number of patients with iliac vein thrombosis who might be eligible for inclusion into a theoretic randomized controlled trial of endovascular therapy, each record was carefully reviewed for exclusion criteria [12,13]. These exclusion criteria were derived from two contemporary randomized controlled trials (Table 1). Where criteria differed between the two trials, the more liberal criteria were chosen in order to bias inclusion toward maximal study participation. All potential participant enrollments into this theoretic trial were adjudicated using a priori study criteria by a committee comprised of three clinicians (E. Wysokinska, W. Wysokinski and R. D. McBane) and one interventional radiologist (H. Bjarnason) blinded to eventual interventional status and clinical outcome.

Table 1.   Inclusion and exclusion criteria for randomization trial participation
Inclusion criteria
 Symptomatic proximal DVT involving the iliac vein from the  confluence of the IVC to the bifurcation of the common  femoral vein
 Age 16–75 years
Exclusion criteria
 Bleeding diathesis (active bleeding, recent (< 3 month) GI  bleeding, severe liver dysfunction)
 Limb-threatening circulatory compromise (i.e. phlegmasia  cerulea dolens).
 Hemoglobin < 8.0 mg dL−1
 Thrombocytopenia < 80 000 mL−1
 Severe renal impairment (estimated GFR < 30 mL min−1)
 Severe hypertension (systolic > 180 mm Hg or  diastolic > 100 mm Hg)
 PE with hemodynamic compromise (i.e. hypotension)
 Pregnancy
 Recent surgery or trauma (< 14 days)
 Intracranial hemorrhage history
 Active cancer (metastatic, progressive, or treated within the  last 6 months)
 Life expectancy < 2 years or chronic non-ambulatory status
 Symptom duration more than 21 days
 Recent stroke (< 3 months)

Major event definition and adjudication

The primary efficacy outcome was successful iliac venous recanalization. A major thrombotic event was defined as DVT of the leg, PE or venous thrombosis at an atypical location. DVT had to be confirmed by either duplex ultrasonography, venography, CT, MRI, or pathology examination of thrombus removed at surgery or autopsy. PE had to be confirmed by pulmonary angiography, contrast-enhanced CT, MRI, pathology examination of thrombus removed at surgery or autopsy, or a ventilation-perfusion lung scan interpreted as high probability for pulmonary embolism. A recurrent iliac vein thrombosis was distinguished from the original thrombus by comparing serial imaging modalities. In order to be classified as a recurrent event, there had to be new filling defects evident on the second study that were not appreciated on the original images, or an interval study clearly showing thrombus resolution.

The primary safety end-point was major bleeding. Major bleeding was defined as overt bleeding plus a hemoglobin decrease of ≥ 2 g dL−1 after the procedure or transfusion of ≥ 2 units of packed red blood cells, or intracranial, intraspinal, intraocular, retroperitoneal, pericardial or fatal bleeding [14]. Minor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding.

Statistical analysis

Continuous numerical variables were reported as means with standard deviation. Frequencies were reported where appropriate. Categorical factors were compared between groups treated and not treated with endovascular therapies using the chi-square test for independence. Continuous variables were compared between groups using the Wilcoxon rank-sum test. The 5-year cumulative incidence rates for first events of venous thrombosis recurrence, major bleeding and survival were estimated using the Kaplan–Meier product limit method using Jmp software (Cary, NC, USA).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

Demographic characteristics

Three hundred and ninety-four patients with incident lower extremity DVT were diagnosed at the Mayo Clinic during the 2005 calendar year. Ninety-five patients had radiographic evidence of iliac vein involvement (Table 2). Of these, 59 patients had their initial diagnosis made at the Mayo Clinic. The rest were referred with this diagnosis having been made at their primary medical institution. The majority of diagnoses were made by ultrasound (83%). Multiple imaging modalities were used to confirm the diagnosis in 37% of patients. These included contrast CT (37%), venography (16%) and MRI (7%).

Table 2.   Baseline clinical characteristics of patients with iliac vein thrombosis
VariableTotal (n = 95)Intervention (n = 31)Non-intervention (n = 64)P-value
Age mean (± SD)55.5 (19.7)50.5 (18.7)57.9 (19.8)0.09
Women48.0%42%52%0.39
Thrombus location, n (%)
 IVC25 (26%)14 (41%)11 (17%)0.0056
 Iliac95 (100%)31 (100%)64 (100%)1.00
 Femoral86 (91%)26 (84%)60 (94%)0.14
 Popliteal54 (57%)14 (45%)40 (63%)0.12
 Tibial 9 (9%) 2 (7%) 7 (11%)0.71
Side involved (%)
 Left55%58%52%0.66
 Right22% 6%30%0.016
 Bilateral23%35%19%0.12
Unprovoked, n (%)19 (20%) 4 (13%)15 (23%)0.12
Surgery/trauma, n (%)22 (23%) 5 (16%)17 (27%)0.31
Immobility, n (%)12 (13%) 5 (16%) 7 (11%)0.52
Hormone, n (%)
 OCP/HRT 7 (7%) 4 (13%) 3 (5%)0.21
 Pregnancy 5 (5%) 2 (6%) 3 (5%)0.66
Malignancy, n (%)27 (28%) 7 (23%)20 (31%)0.47
Thrombophilia (No. tested)2114 70.0014
Protein C (%) 0 0 0
Protein S (%) 0 0 0
Antithrombin (%) 0 0 0
Factor V Leiden (%)1329 5
Prothrombin G20210A (%) 2 3 0
Lupus Anticoag/APS (%) 1 0 2
Previous VTE (%)24 (25%)12 (40%)10 (16%)0.018

Thirty-one patients (33%) underwent an intervention for iliac venous recanalization (Table 2). By definition, iliac venous involvement was present in all patients. Venous thrombus extending beyond the iliac segment was quite common. Those undergoing an intervention were more likely to have IVC involvement compared with those not undergoing an intervention. Ninety-one per cent of the overall group had accompanying femoral vein thrombosis and more than 50% had popliteal vein involvement. The extent of venous thrombosis, however, was similar for those patients undergoing and not undergoing an intervention.

Acquired risk factors, including surgery, trauma, immobility, hormonal stimulation and underlying malignancy, were similar between groups. Relatively few patients in each group underwent thrombophilia testing. Of those tested, patients undergoing an intervention had a significantly higher percentage of factor V Leiden, including two patients with homozygous mutations and one patient with combined heterozygous factor V Leiden and prothrombin G20210A mutations.

Suitability for trial randomization

Of the 95 patients with iliac vein thrombosis, nine patients would have been suitable for randomization in a trial of thrombolytic therapy based on criteria published for two contemporary trials (Table 3). Of note, both the ATTRACT and CavenT trials would also include patients with isolated femoral vein thrombosis without iliac vein involvement. Of the remaining 86, 19 would not have been eligible for study randomization because of the age criteria alone. Of those meeting the age criteria, all had at least one of the exclusion criteria and 27 patients had two or more exclusion criteria. Among these, symptom duration exceeding 3 weeks (= 28) and active malignancy (n = 24) were the most common. Short life expectancy and recent surgery were also common exclusions. No patients would have been excluded for uncontrolled hypertension.

Table 3.   Distribution of exclusion criteria by interventional status
Variable nIntervention (n = 31)Non-intervention (n = 64)P-value
Exceeded age criteria4150.29
Active cancer (metastatic, progressive, or treated within the last 6 months)7260.11
Symptom duration more than 21 days13150.09
Limb-threatening circulatory compromise (i.e. phlegmasia cerulea dolens)110.54
Bleeding diathesis (active bleeding, recent (< 3 month) GI bleeding, severe liver dysfunction)410.04
Thrombocytopenia < 80 000 mL−1040.31
Severe renal impairment (estimated GFR < 30 mL min−1)510.66
Recent stroke/TIA021.0
PE with hemodynamic compromise (i.e. hypotension)110.54
Pregnancy020.54
Recent surgery or trauma (< 14 days)3100.54
Life expectancy < 2 years or chronic non-ambulatory status2110.21
History of CNS bleed150.66
Asymptomatic020.54

To discern the differences between actual clinical practise and potential trial participation, exclusion criteria were reviewed for those 31 patients who had an intervention. Seventy-seven per cent had at least one potential exclusion criteria for trial participation. The most common exclusion criteria included prolonged symptom duration, renal impairment, advanced age and active cancer. Malignancy was more prevalent in those patients not undergoing an intervention. Yet, nearly 16% of those patients undergoing iliac venous recanalization had evidence of active malignancy. There were only two cases with no identifiable contraindication that did not have intervention. Neither patient had sufficient symptomatology to warrant an intervention.

Interventions and outcomes

The technical success of the 31 patients undergoing an intervention was 97% (Table 4). Mean duration of follow-up was 1.6 years (± 1.4 years). Most patients underwent some combination of mechanical thrombectomy, thrombolysis and angioplasty with stenting. Two patients underwent systemic thrombolytic therapy. Five patients underwent surgical thrombectomy. Vena caval filters were placed in seven patients. Four of these filters were retrievable devices, of which three were ultimately removed at 6, 19 and 20 days, respectively. None of the retrieved filters had evidence of embolized thrombus.

Table 4.   Interventions performed
ProcedureIntervention (n = 31)
Mechanical thrombectomy7
Thrombolysis16
 Catheter-directed14
 Systemic2
Venoplasty22
 Stent20
IVC filter7
 Temporary4
Surgical5

The 5-year cumulative survival free of recurrent venous thrombosis was compared by intervention status (Fig. 1A). Warfarin therapy was prescribed to 31 patients in the intervention group and 52 patients in the non-intervention group. There were 11 recurrent venous thrombotic events. Seven recurrent events occurred in the intervention group (four symptomatic). Survival free of venous thrombosis recurrence was higher (= 0.018) for the non-intervention group compared with those that had an intervention. Within the intervention group, six of the seven venous thrombi recurred on warfarin therapy. Each thrombus recurred within the iliofemoral venous segment initially involved. In the non-intervention group, all four recurrences occurred despite warfarin therapy. These included one PE, one upper extremity DVT, one leg DVT and one thrombus propagation.

image

Figure 1.  Five-year comparative outcomes. The 5-year cumulative rates of venous thrombosis recurrence (Panel A), major hemorrhage (Panel B) and survival (Panel C) were compared for those undergoing (solid line) and those not undergoing (dashed line) a venous intervention.

Download figure to PowerPoint

Major bleeding occurred in nine individuals; only one was from the intervention group. Bleeding events occurred sporadically over time. Seven of these nine patients suffered bleeding on anticoagulant therapy; five on warfarin, one on enoxaparin and one following tPA therapy. The 5-year cumulative survival free of major bleeding did not differ by treatment group (Fig. 1B).

There were 32 deaths overall. Eight deaths occurred in patients in the intervention group and 24 in the non-intervention group. Eighteen deaths occurred in patients with underlying cancer. Four patients had underlying renal failure. There was no difference in the mortality rates (Fig. 1C) between the two groups.

Comparing patient outcomes by timing of presentation (< 21 days vs. > 21 days), there were no differences in major hemorrhage (3 vs. 0), recurrence (4 vs. 1) or mortality rates (5 vs. 3).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

The principal finding of this study is an estimate of the number of patients with iliac vein thrombosis seen annually at a single tertiary care center. With the removal of referred patients, the incidence of iliac vein thrombosis was 15% (59/394). This percentage is likely to underestimate the true incidence because iliac venous segments are not routinely imaged as part of ultrasound practise. Isolated iliac vein involvement may be found incidentally by CT or MRI imaging or specifically sought after when preceded by strong clinical suspicion. With an active interventional program for venous disease, one might anticipate number enrichment from external referrals (nearly 40% in this experience). Without knowledge of these numbers, trials of endovascular therapies for this disease can neither be appropriately designed nor adequately completed. These limitations were highlighted by a meta-analysis performed by the Cochrane Peripheral Vascular Diseases Group [1]. In this report, 12 randomized controlled studies of thrombolysis were identified. Yet of these, eight studies had < 50 participants and only one had more than 100 patients. Only two studies described a power assessment. Furthermore, combining trials of systemic, regional and catheter-directed thrombolysis complicates the interpretation of this meta-analysis.

The second finding of this study is an estimate of the percentage of these patients with iliac vein thrombosis who could potentially be randomized based on eligibility criteria from two current trials [12,13]. A large percentage of these patients (91%) had at least one exclusion, leaving a relatively small number of patients eligible for trial participation. Furthermore, trial eligibility criteria do not appear to recapitulate real world experience. Of the 31 patients undergoing an intervention, 75% had at least one exclusion criteria. The biggest category for trial exclusion was prolonged symptom duration, present in nearly 30%. Yet, despite exceeding the 21-day optimal time window for intervention, the technical success for venous recanalization exceeded 90%. Therefore, this time window may unnecessarily exclude patients who may benefit from this therapy. ‘Late’ referrals may represent an educational gap that could be remedied. Often patients are referred only when conservative treatment fails to improve symptoms. Current therapies include a combination of thrombolytic therapy, anticoagulants and mechanical clot dissolution [11]. Indeed, a new term ‘pharmacomechanical thrombolysis’ has been introduced to better describe this therapeutic evolution. Therefore, future trials must specifically define the nature of the proposed intervention and the associated patient characteristics in order to compare trials and understand the contribution of each component of therapy. For example, acute thrombus treatment might include predominantly thrombolytic therapy, whereas subacute or chronic venous occlusion may require predominantly mechanical intervention. From a trial design standpoint, expanding the window for intervention may increase study participation, yet at the same time add complexity to data interpretation. Furthermore, extending the interventional window may result in the inclusion of patients who have already suffered irreversible valvular damage, thus negating the post-thrombotic benefits of the open iliac vein.

Another major exclusion was active cancer, present in 25% of patients. For randomized trial design purposes, this exclusion may be justified. Patients with active cancer are prone to both bleeding and thrombosis complications. Sufficient survival is required to interpret the impact of the intervention on the postphlebitic syndrome outcome. The overall 5-year mortality rate in this study was 33%, more than half of deaths were cancer related. Furthermore, each cancer is unique with regards to prognosis and response to surgery, chemotherapy and radiation therapy. The reality of clinical practise is that cancer patients do present with iliac vein thrombosis and some survive their cancer to suffer the ravages of postphlebitic syndrome.

The third most common exclusion was patient age exceeding 75 years. Venous thrombosis is a disease of the elderly. With the aging of our society, we should anticipate seeing more elderly patients with the postphlebitic syndrome. Exclusion of elderly patients presumably stems from safety concerns related to major bleeding complications. However, major bleeding in the entire cohort was very low and did not differ by treatment allocation. These perceived risks therefore don’t appear to be substantiated. The second reason for excluding these patients might stem from the idea that given their age, postphlebitic syndrome might be less of a concern. In these individuals, the morbidity of severe postphlebitic syndrome may be the factor limiting their ability to live independently. With fewer coping skills and resources, these may be the patients benefiting most from this type of procedure. The risks of major bleeding must be carefully weighed against the potential benefit of the procedure. Finally, the chronologic and physiologic age may differ considerably from one elderly patient to another and decisions must be individualized.

Two asymptomatic patients with iliac vein thrombosis did not undergo an intervention despite having no potential contraindications. Although asymptomatic at initial clinical evaluation, freedom from future postphlebitic symptoms cannot be guaranteed. Patients with thrombosis involving the iliac venous segments are more prone to develop the post-thrombotic syndrome relative to patients with thrombus of more distal location [15–18]. Indeed, as many as 80% of patients with iliac vein thrombosis will develop this syndrome, with nearly 50% suffering disabling venous claudication [16]. Iliofemoral venous thrombosis carries a more than 2-fold increased risk of recurrent thrombosis [19]. Moreover, recurrent, ipsilateral DVT has been shown to be an important predictor of the post-thrombotic syndrome [20]. Endovascular treatment is believed to prevent the postthrombotic syndrome in such patients. With the advancement of modern techniques such as catheter-directed thrombolysis the risk of major hemorrhagic complications is relatively low. Whether all patients with proximal DVT irrespective of symptoms should undergo screening of iliac vein involvement for potential endovascular treatment remains unclear. Our ultrasound protocol includes documentation of the most proximal extent of all visualized thrombi, including imaging iliac venous segments and the inferior vena cava where indicated. Spectral Doppler techniques with and without Valsalva maneuvers are performed at the common femoral vein and sapheno-femoral junction to provide an indirect assessment of the patency of more cephalad venous segments. Our general approach to patients with acute iliac venous thrombosis is to offer endovascular therapy if there is no contraindication for thrombolysis. This approach is predicated on the fact that there is no current tool available to predict which patients will go on to suffer the postphlebitic syndrome. For patients with subacute to chronic presentation with persistent iliac venous occlusion, we would consider endovascular intervention if symptoms are sufficiently limiting to warrant such a procedure.

The 5-year outcomes included an increased rate of venous thrombosis recurrence in those patients undergoing an intervention. Thrombus recurrence, however, must be distinguished from primary and secondary venous patency. Because all events recurred at the site of prior intervention, this unfairly biases the interpretation of these results against the intervention. Clearly without venous recanalization, there would be no venous segment available for re-occlusion. It should also be noted, however, that isolated iliac vein involvement was rare. Secondly, interventional patients are carefully followed both clinically and radiologically for recurrent events, including biannual ultrasound and venous plethysmography. Observer bias therefore favors the non-intervention group regarding thrombus recurrence. Third, symptomatic and radiographic recurrences must be differentiated. Seven patients in the intervention group had thrombus recurrence yet only four caused symptoms. If the patient experienced a symptomatic recurrence then this would be considered a procedural setback. If the recurrence produces no symptoms, then it could be argued that the goal of postphlebitic syndrome prevention had been maintained. Given limitations of retrospective analysis and incomplete follow-up at our vascular center, we were not able to determine with certainty the rate of postphlebitic syndrome in our study.

The CaVenT study group recently published the short-term outcomes of their trial of catheter-directed thrombolysis vs. anticoagulant therapy in 103 patients with acute proximal venous thrombosis [21]. Of patients randomized to catheter-directed therapy, 88% achieved either complete or partial (50–90%) lysis. Major bleeding occurred in one patient and two had clinically relevant bleeding related to the procedure. After 6 months, iliofemoral patency was twice as frequent in the invasive treatment arm compared with the conservative arm. Still to be determined is whether this form of therapy will lead to improved functional outcome.

The CavenT trial design has completed its enrollment of 200 patients from 24 centers after 4 years. The ATTRACT trial is designed to enroll 692 patients from 46 centers over a 30-month period. Assuming that large tertiary centers with expertise in venous interventions would see, on average, 10 patients per year with iliac vein thrombosis eligible for trial participation, and assuming that the trial enrollment would occur over a period of 30 months, one would need to build a consortium of at least 28 centers. This is assuming that all eligible patients would agree to participate and that all attending physicians would agree to randomization. One might therefore anticipate 50–70% recruitment of all eligible participants. With 46 centers and 30-month anticipated enrollment, between 575 and 805 participants would be expected. The ATTRACT trial might therefore be feasible without expanding recruitment to isolated femoral vein thrombosis [12,13]. Common femoral vein thrombosis has recently been proposed as an important contributing variable for the post-thrombotic syndrome [22]. Based on the experience of Kahn et al., femoral involvement without iliac involvement will predominate (83% of patients in their study). We believe that if femoral venous thrombosis without iliac involvement is included and analyzed together with iliac vein thrombosis, there is a risk of missing a significant clinical improvement with endovascular therapy. Given the complexity and cost of these trials, the possibility of a negative trial would be a major setback. The CavenT trial included patients with isolated femoral vein thrombosis, which made up half of the enrollees. Disappointingly, femoral venous insufficiency did not differ between the two treatment arms at 6 months [21].

Several important limitations of this study should be noted. First, this theoretic trial differs considerably from both the ATTRACT and CavenT trials, which included isolated femoral vein thrombosis in their trial designs. Cautious optimism is warranted regarding the trial outcomes with respect to improvement of the postphlebitic syndrome. Second, study outcomes are retrospective and thus cannot supplant any prospective randomized trial data. These findings, however, represent a ‘real-world’ experience at a center devoted to the care of patients with venous disease. Third, the sample size is quite small relative to these two ongoing or completed trials.

In summary, despite a philosophy of aggressive treatment for iliac vein thrombosis at this large tertiary care center, the number of cases that could be potentially randomized is relatively small, with few ‘overlooked’ patients. Randomized controlled trials therefore will require multicenter cooperation. Patient inclusion and exclusion criteria must be carefully considered in future trial design, in order to better recapitulate clinical practise. In general, we favor limiting inclusion to patients with iliac vein involvement while at the same time broadening the patient-specific inclusion/exclusion criteria. This could include older symptomatic patients who are otherwise healthy, oncology patients with reasonable anticipated survival, and patients with symptoms extending beyond 21 days. Without these considerations, clinicians may be left without useful guidelines applicable for the majority of patients presenting with this disease.

Disclosure of Conflict of Interests

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References

The authors state that they have no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Disclosure of Conflict of Interests
  8. References
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