Abstract
Purpose:
To evaluate relationships between immediate venographic results and clinical outcomes of pharmacomechanical catheter-directed venous thrombolysis (PCDT).
Materials and Methods:
Venograms from 317 acute proximal DVT patients who received PCDT in a multicenter randomized trial were reviewed. Quantitative thrombus resolution was assessed by independent readers using a modified Marder scale. The physician operators recorded their visual assessments of thrombus regression and venous flow. These immediate post-procedure results were correlated with patient outcomes at 1, 12, and 24 months.
Results:
PCDT produced substantial thrombus removal (p < 0.001 for pre-PCDT versus post-PCDT thrombus scores in all segments). At procedure end, spontaneous venous flow was present in 99% of iliofemoral venous segments and in 89% of femoral-popliteal venous segments. For the overall proximal DVT population, and for the femoral-popliteal DVT subgroup, post-PCDT thrombus volume did not correlate with 1-month or 24-month outcomes. For the iliofemoral DVT subgroup, over 1 and 24 months, symptom severity scores were higher (worse) and venous disease-specific quality of life (QOL) scores were lower (worse) in patients with greater post-PCDT thrombus volume, with the difference reaching statistical significance for the 24-month Villalta PTS severity (p=0.0098). Post-PCDT thrombus volume did not correlate with 12-month valvular reflux.
Conclusion:
PCDT successfully removes thrombus in acute proximal DVT. However, the residual thrombus burden at procedure end does not correlate with the occurrence of PTS during the subsequent 24 months. In iliofemoral DVT, lower residual thrombus burden correlates with reduced PTS severity and possibly also with improved venous QOL and fewer early symptoms.
Introduction
Patients with proximal deep vein thrombosis (DVT) frequently (40%-50%) develop the post-thrombotic syndrome (PTS) (1). PTS may cause daily limb pain, swelling, heaviness, and fatigue, with progression to stasis dermatitis and venous ulcers. These sequelae frequently impair patients’ long-term health-related quality of life (QOL) (2).
The rationale for catheter-directed thrombolysis (CDT) for DVT has been largely predicated on the “open vein hypothesis”, which postulates that early thrombus removal may facilitate long-term venous patency, preserve venous valve function, reduce PTS, and improve QOL. However, of three recent randomized controlled trials (RCTs) that evaluated CDT and related therapies for proximal DVT, none provided strongly confirmatory findings (i.e., both prevention of PTS and improvement of long-term QOL) to justify widespread use of CDT as first-line therapy (3–6).
In the largest RCT, the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial, pharmacomechanical catheter-directed thrombolysis (PCDT) reduced the volume of thrombus but not the occurrence of PTS. However, PCDT did reduce PTS severity and improve QOL in the subgroup of patients with acute iliofemoral DVT (5,7). Substantial venous thrombus was present in both the PCDT (about 40% of vein segments non-compressible) and No-PCDT (about 60% of vein segments non-compressible) treatment groups on follow-up sonography at 1 month and 12 months post-randomization; 1-month common femoral vein non-compressibility showed significant (P<0.01) correlations with 2-year PTS, moderate-or-severe PTS, and impaired QOL (8). In the current analysis of the ATTRACT dataset, we evaluate and correlate the immediate venographic results of PCDT with subsequent clinical outcomes.
Materials and Methods
Study Design and Patients
The ATTRACT Trial was a Phase III, multicenter, open-label, assessor-blinded, randomized clinical trial. The study is registered at www.clinicaltrials.gov. Patients provided written informed consent to participate. The study was approved by the institutional review boards of all participating clinical centers. Those who designed the study, collected/analyzed the data, drafted the paper, and decided to publish it will be specified in the final un-blinded version.
Patients with acute symptomatic proximal DVT extending above the popliteal vein were enrolled at 56 U.S clinical centers, and randomly assigned to receive PCDT and anticoagulation or anticoagulation alone. Randomization was stratified by clinical center and thrombus extent (whether or not the common femoral vein was compressible). Study eligibility criteria, methods of study conduct, use of anticoagulation and compression therapy, description of clinical outcomes assessment, and the main study outcomes have been previously published (5,7).
This analysis focuses exclusively on patients who were assigned to, and actually received, PCDT therapy. Comparisons with the control arm could not be performed since those patients did not undergo venography. As seen in Figure 1, 337 patients were randomized to the PCDT Arm. After exclusion of patients who did not have qualifying proximal DVT (n=1), did not undergo PCDT within 7 days (n=11), or had no thrombus on venography (n=8), 317 patients had their venograms included in this per-protocol analysis. Table 1 shows their baseline characteristics.
Figure 1 -. Patient Flow (CONSORT) Diagram.
Patient flow and outcomes data capture in the PCDT Arm of the ATTRACT Trial (per-protocol analysis population).
Table 1.
Baseline characteristics for participants who received initial PCDT*
| PCDT Arm of ATTRACT Trial | |||
|---|---|---|---|
| Overall (N=317) | IF*** (N=200) | FP*** (N=117) | |
| Age (years), median (range) | 51.0 (16.0, 75.0) | 51.0 (16.0, 75.0) | 52.0 (16.0, 75.0) |
| Male, n (%) | 192/317 (61%) | 111/200 (56%) | 81/117 (69%) |
| White, n (%) | 251/317 (79%) | 189/200 (80%) | 92/117 (79%) |
| Hispanic or Latino, n (%) | 15/317 (5%) | 13/200 (7%) | 2/117 (2%) |
| BMI (kg/m2), median (range) | 30.9 (18.4, 59.6) | 30.9 (18.4, 57.6) | 30.7 (19.9, 59.6) |
| eGFR (ml/min), median (range) | 78.0 (39.0, 182.0) | 80.0 (48.0, 182.0) | 75.4 (39.0, 135.0) |
| DVT Left Leg, n (%) | 199/317 (63%) | 122/200 (61%) | 77/117 (66%) |
| Any Previous DVT, n (%) | 70/317 (22%) | 52/200 (26%) | 18/117 (15%) |
| Any Previous Ipsilateral DVT, n (%) | 4/317 (1%) | 4/200 (2%) | 0/117 (0%) |
| Non-compressible CFV, n (%)** | 175/300 (59%) | 147/186 (79%) | 28/114 (25%) |
| Non-compressible FV, n (%)** | 279/300 (93%) | 168/186 (90%) | 111/114 (98%) |
| Non-compressible PV, n (%)** | 260/300 (87%) | 154/186 (80%) | 106/114(96%) |
BMI=Body Mass Index, eGFR=Estimated Glomerular Filtration Rate, DVT=Deep Vein Thrombus, CFV=Common Femoral Vein, FV=Femoral Vein, PCDT=Pharmacomechanical Catheter-Directed Thrombolysis, PV=Popliteal Vein, IF = Iliofemoral, FP = Isolated Femoral Popliteal, SD=Standard Deviation
Per protocol dataset. 10 patients underwent venography but did not undergo PCDT – because this study is focused on mechanistic questions, they were excluded from this analysis.
Data is from pre-randomization baseline ultrasounds
For these analyses, patients were categorized in the IF and FP subgroups based on thrombus extent on the pre-PCDT venogram, irrespective of the findings on the baseline ultrasound.
Venography and PCDT Procedures
Patients underwent hand-injected catheter venography of the proximal veins of the index limb and pelvis immediately before PCDT and then immediately after PCDT and any adjunctive procedures were completed. If there was good inflow into the popliteal vein, the Trellis-8 device (Medtronic, Minneapolis, MN - Technique A) or the AngioJet device (Boston Scientific, Marlborough, MA – Technique B) was used to administer the thrombolytic drug (Activase, recombinant tissue plasminogen activator [rt-PA), Genentech, South San Francisco, CA). Patients with poor or absent inflow into the popliteal vein first underwent catheter-directed rt-PA infusion (Technique C) using a multi-sidehole catheter. After initial thrombolysis as above, physicians were instructed to continue rt-PA infusion until at least 90% of the thrombus was removed and there was anterograde flow by visual assessment, the protocol’s dose limits (35 mg rt-PA total, 24-30 hours infusion) were reached, or a complication occurred.
Assessment of Venograms
Static images of the pre-PCDT and post-PCDT venograms were transmitted on digital media to an independent core laboratory at the study’s data coordinating center, where experienced physician readers graded the venograms using the elements of the Marder score that correspond to the proximal veins (9). A “total thrombus score” was summed from component scores for the popliteal (4 points), femoral (10 points), common femoral (4 points), and iliac (6 points) veins (hence, total possible score for a limb with complete thrombosis was 24 points) (Table E1). An “iliofemoral segment sub-score” (total possible 10 points, summed from the iliac and common femoral vein component scores) and a “femoral-popliteal segment sub-score” (total possible 14 points, summed from the femoral and popliteal vein scores) were also computed.
Immediately after PCDT, the endovascular operators also documented from the venograms if there was spontaneous anterograde flow in the iliofemoral and/or femoral-popliteal venous segments, and the proportion of thrombus removed (> 90%, 75-90%, 50-75%, or < 50%).
Assessment of Clinical Outcomes
As described elsewhere (5), PTS was assessed at follow-up visits between 6 and 24 months post-randomization by clinician examiners who were blinded to treatment allocation. PTS was counted if there was a Villalta Scale score ≥ 5, a venous ulcer, or an unplanned endovascular procedure during follow-up to treat severe venous symptoms (10). Moderate-or-severe PTS was defined as a Villalta score ≥ 10 or a venous ulcer. PTS severity was graded with the continuous Villalta Scale [range 0-33] and the modified Venous Clinical Severity Scale [VCSS, range 0-27]; for both scales, higher scores indicate more severe PTS (11). Venous disease-specific QOL was patient-reported using the Venous Insufficiency Epidemiologic and Economic Quality of Life Survey (VEINES-QOL) (12). Early DVT symptoms were characterized by a Likert pain scale (13) (range 0-7, higher worse), the Villalta Scale, and VEINES-QOL at baseline and 1 month. Thrombus extent was defined by compression ultrasound at baseline and at 1 month follow-up. In addition, in 5 pre-selected Clinical Centers, 142 consecutive patients had venous duplex ultrasound at 12 months, including valvular reflux assessment (flow reversal > 0.5 seconds)..
Statistical Analysis
The analysis population consisted of patients who had DVT at enrollment, were randomized to the PCDT Arm, had thrombus on venography, and received initial PCDT as assigned. Since the venograms more accurately depicted the thrombus extent at the time of PCDT (compared with the pre-randomization ultrasounds done several days earlier), these analyses categorize patients in anatomic subgroups based on whether the pre-PCDT venogram showed thrombus in the iliac and common femoral veins (“iliofemoral DVT”), or not (“femoral-popliteal DVT”) (14).
The differences in total and segmental thrombus scores and sub-scores between pre-PCDT and post-PCDT venograms were evaluated using paired t-tests for the overall cohort, iliofemoral DVT subgroup, femoral-popliteal DVT subgroup, and the three PCDT techniques. The associations between the continuous immediate-post-PCDT total thrombus scores, iliofemoral segment sub-scores, and femoral-popliteal segment sub-scores with outcomes used analysis of covariance (ANCOVA) for continuous outcomes, adjusted for baseline status, and chi square tests for categorical outcomes. The ANCOVA method was felt to be advantageous since the amount of change in these outcomes could potentially be limited by the measures themselves, and may have different meaning at different points in each scale. Testing for the overall cohort, and for the iliofemoral DVT and femoral-popliteal DVT subgroups, was conducted separately.
To further explore the relationships between residual thrombus and clinical outcomes, we reviewed the distribution of thrombus scores, considered the clinical relevance of potential cut-points, and categorized patients into three groups by their total thrombus score on the immediate-post-PCDT venograms: (a) complete lysis (total thrombus score 0); (b) mild residual thrombus occupying < 25% of the veins’ volume (0 < total thrombus score < 6); and (c) substantial residual thrombus occupying ≥ 25% of the veins’ volume (total thrombus score ≥ 6).
Differences between these groups were evaluated using an ANCOVA for continuous clinical outcomes and chi square test for categorical outcomes. Pairwise comparisons were examined using a Tukey post-hoc adjustment if the overall F test was significant. Subgroup comparisons in age (<65 years, ≥65 years), sex (male, female), ethnicity (Hispanic, non-Hispanic), race (African-American, White, Other), body-mass index (< 25, 25-30, >30 kg/m2), leg symptom duration (<1 week, > 1 week), side of DVT (left, right), presence of major provoking DVT risk factor (yes, no), and history of previous DVT or PE (yes, no) for complete thrombus removal (versus incomplete removal were conducted using separate logistic regression and the odds ratios (OR) and 95% confidence interval are reported. Differences in the percent thrombus removal between these subgroups were also evaluated using Wilcoxon tests.
A two-sided P value of 0.01 or lower was considered statistically significant for all analyses to account for multiple testing. All analyses were conducted in SAS v9.4 (SAS Institute, Cary NC).
Results
Thrombus Removal on Independently Adjudicated Venograms
For all vein segments, PCDT led to substantial thrombus volume reduction, shown by reduction of the iliofemoral segment sub-score (p < 0.001), femoral-popliteal segment sub-score (p < 0.001), and total thrombus score (p < 0.001) (Table 2). This was true for the entire PCDT Arm cohort, for iliofemoral DVT and femoral-popliteal DVT, and for all three PCDT methods (Table 3). For the iliofemoral segment, the mean post-PCDT thrombus score was 0.7 points ± 1.6, corresponding to 7% of the volume of that segment (total possible 10 points) (Table 2). For the femoral-popliteal segment, the mean post-PCDT thrombus score was 2.0 points ± 2.9, corresponding to 14% of the volume of that segment (total possible 14 points) (Table 2).
Table 2.
Effect of PCDT upon Thrombus Volume and Venous Patency
| Independent Core Lab Assessment of Venograms** | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| All | IF | FP | |||||||
| Thrombus Scores* | Pre-lysis (N=317) | Post-lysis (N=317) | P-value | Pre-lysis (N=200) | Post-lysis (N=200) | P-value | Pre-lysis (N=117) | Post-lysis (N=117) | p-value |
| Iliac, mean (SD) | 1.6 (2.4) | 0.3 (1.0) | - | 2.6 (2.6) | 0.5 (1.2) | - | 0.0 (0.0) | 0.0 (0.0) | - |
| CFV, mean (SD) | 1.7 (1.7) | 0.4 (0.8) | - | 2.8 (1.2) | 0.6 (1.0) | - | 0.0 (0.0) | 0.0 (0.0) | - |
| Iliac and CFV subscore, mean (SD) | 3.3 (3.7) | 0.7 (1.6) | <0.001 | 5.4 (3.2) | 1.1 (1.9) | <0.001 | 0.0 (0.0) | 0.0 (0.0) | 0.99 |
| Femoral, mean (SD) | 6.0 (3.6) | 1.3 (2.2) | - | 6.2 (3.8) | 1.5 (2.4) | - | 5.7 (3.2) | 1.1 (1.8) | - |
| Popliteal, mean (SD) | 2.2 (1.8) | 0.7 (1.1) | - | 1.8 (1.8) | 0.6 (1.0) | - | 2.8 (1.5) | 0.9 (1.2) | - |
| Femoral and Popliteal subscore, mean (SD) | 8.1 (4.8) | 2.0 (2.9) | <0.001 | 7.9 (5.2) | 2.0 (3.1) | <0.001 | 8.5 (4.0) | 1.9 (2.5) | <0.001 |
| Total Thrombus Score, mean (SD) | 11.3 (5.7) | 2.7(3.6) | <0.001 | 13.2 (5.9) | 3.1 (4.1) | <0.001 | 8.5 (4.0) | 1.9 (2.5) | <0.001 |
| End-of-Procedure Operator Assessment of Venograms | |||||||||
| Anterograde flow in iliac and CFV, n (%) | 313/317 (99%) | 196/200 (98%) | 117/117 (100%) | ||||||
| Anterograde flow in FV and PV, n (%) | 281/317 (89%) | 177/200 (89%) | 104/117 (89%) | ||||||
| Estimate clot lysis, n (%) | |||||||||
| >90% | 234/317 (74%) | 144/200 (72%) | 90/117 (77%) | ||||||
| 75-90% | 46/317 (15%) | 29/200 (15%) | 17/117 (15%) | ||||||
| 50-75% | 23/317 (7%) | 16/200 (8%) | 7/117 (6%) | ||||||
| < 50% | 14/317 (4%) | 11/200 (6%) | 3/117 (3%) | ||||||
BMI=Body Mass Index, eGFR=Estimated Glomerular Filtration Rate, DVT=Deep Vein Thrombus CFV=Common Femoral Vein, FV=Femoral Vein, PCDT=Pharmacomechanical Catheter-Directed Thrombolysis, PV=Popliteal Vein, SD=Standard Deviation, IF = Iliofemoral, FP = Isolated Femoral Popliteal
Marder scores (range 0 [no thrombus] to 24 [complete thrombosis])
15 patients initially stratified in the FP group based on pre-randomization ultrasound but were found to have thrombus in the iliofemoral segment, so they were considered to belong to the IF group in this analysis
Table 3.
Immediate Thrombus Removal and Venous Patency by Thrombolytic Technique Used
| Independent Core Lab Assessment of Venograms | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Thrombus Scores* | Technique A Trellis (N=50) | p-value | Technique B Angiojet (N=75) | p-value | Technique C Infusion-First (N=192) | p-value | |||
| Pre-lysis | Post-lysis | Pre-lysis | Post-lysis | Pre-lysis | Post-lysis | ||||
| Iliac, mean (SD) | 2.5 (2.7) | 0.5 (1.2) | - | 1.7 (2.4) | 0.3 (0.9) | - | 1.3 (2.3) | 0.3 (0.9) | - |
| CFV, mean (SD) | 2.4 (1.6) | 0.6 (0.8) | - | 1.7 (1.7) | 0.4 (0.9) | - | 1.6 (1.7) | 0.4 (1.0) | - |
| Iliac and CFV subscore, mean (SD) | 4.9 (3.7) | 1.1 (1.7) | <0.001 | 3.3 (3.5) | 0.6 (1.6) | <0.001 | 2.9 (3.6) | 0.6 (1.6) | <0.001 |
| Femoral, mean (SD) | 4.9 (3.9) | 1.0 (1.9) | - | 3.8 (3.3) | 0.7 (1.6) | - | 7.1 (3.1) | 1.7 (2.3) | - |
| Popliteal, mean (SD) | 1.3 (1.8) | 0.3 (0.8) | - | 1.4 (1.6) | 0.4 (0.9) | - | 2.7 (1.6) | 0.9 (1.2) | - |
| Femoral and Popliteal subscore, mean (SD) | 6.1 (5.1) | 1.2 (2.4) | <0.001 | 5.1 (4.3) | 1.1 (2.2) | <0.001 | 9.7 (4.1) | 2.5 (3.1) | <0.001 |
| Total Thrombus score, mean (SD) | 10.8 (6.7) | 2.3 (2.9) | <0.001 | 8.4 (4.5) | 1.7 (2.8) | <0.001 | 12.6 (5.5) | 3.1 (4.0) | <0.001 |
| End-of-Procedure Operator Assessment of Venograms | |||||||||
| Anterograde flow in iliac and CFV, n (%) | 47/50 (94%) | - | 75/75 (100%) | - | 191/192 (99%) | - | |||
| Anterograde flow in FV and PV, n (%) | 46/50 (92%) | - | 71/75 (95%) | - | 164/192 (85%) | - | |||
| Estimate of clot lysis, n (%) | - | - | - | ||||||
| >90% | 40/50 (80%) | 56/75 (75%) | 138/192 (72%) | ||||||
| 75-90% | 4/50 (8%) | 9/75 (12%) | 33/192 (17%) | ||||||
| 50-75% | 4/50 (8%) | 6/75 (8%) | 13/192 (7%) | ||||||
| < 50% | 2/50 (4%) | 4/75 (5%) | 8/192 (4%) | ||||||
BMI=Body Mass Index, eGFR=Estimated Glomerular Filtration Rate, DVT=Deep Vein Thrombus, CFV=Common Femoral Vein, FV=Femoral Vein, PCDT=Pharmacomechanical Catheter-Directed Thrombolysis, PV=Popliteal Vein, SD=Standard Deviation
Marder score
Complete thrombolysis (immediate-post-PCDT Marder score of 0) was observed in 88/297 (30%) of the overall proximal DVT population, in 50/184 (27%) of patients in the iliofemoral DVT subgroup, and in 38/113 (34%) of patients in the femoral-popliteal DVT subgroup.
Other than a non-significant suggestion that patients with shorter (< 1 week) symptom duration may have had complete thrombolysis more frequently (35% versus 23%, p=0.04), other baseline variables did not significantly influence the proportion of patients who had complete thrombolysis (Figure 2A) or the percentage of thrombus removed (Figure 2B).
Figure 2 – Subgroup Analysis of Thrombus Removal with Pharmacomechanical Thrombolysis.
Forest plots depicting thrombus removal among subgroups of PCDT recipients: (A) Proportion of PCDT recipients with complete thrombus removal (odds ratios); (B) median percentage of thrombus removed with PCDT. The horizontal lines represent 95% confidence intervals (CIs).
Operator-Assessed Procedure Success
After PCDT, the endovascular operators reported the presence of anterograde flow in the iliofemoral venous segments of 313/317 (99%) patients, and in the femoral-popliteal venous segments of 281/317 (89%) patients (Table 2). Achievement of ≥ 50% clot lysis was reported in 303/317 (96%) patients, with ≥ 90% clot lysis reported in 234/317 (74%) patients. The results were consistent across both anatomical subgroups and all three PCDT methods used (Table 3).
In the 313 patients with post-PCDT iliofemoral venous patency, point estimates of the 24-month occurrence of PTS (46% versus 60%, p = 0.17) and moderate-or-severe PTS (17% versus 31%, p = 0.06) appeared lower in patients who also had femoral-popliteal venous patency versus those who did not, but did not reach statistical significance (Tables E2 and E3).
Relationship of Immediate Post-PCDT Residual Thrombus to Ultrasound Outcomes
As shown in Table 4, patients with valvular reflux or residual venous non-compressibility at 1 month and 12 months follow-up did not have evidence of less effective PCDT (higher immediate post-PCDT total thrombus scores) than patients who had non-refluxing or compressible veins. An exception was that patients with compressibility of the femoral-popliteal veins at 1 month had a lower volume of immediate-post-PCDT residual thrombus in the same named veins (p=0.006).
Table 4.
Association between Immediate Post-PCDT Residual Thrombus and Ultrasound Outcomes
| Immediate-Post-PCDT Thrombus* Scores | ||||||
| N | Mean (SD) | N | Mean (SD) | p-value^ | ||
| Total Thrombus Score | 1 Month | Yes | No | |||
| CFV compressible | 225 | 2.4 (3.4) | 58 | 3.2 (4.0) | 0.23 | |
| FV/PV compressible | 99 | 2.0 (2.8) | 187 | 2.9 (3.8) | 0.06 | |
| 12 Months | ||||||
| CFV compressible | 54 | 1.9 (2.6) | 8 | 1.6 (1.4) | 0.73 | |
| FV/PV compressible | 28 | 1.7 (2.9) | 34 | 2.1 (2.0) | 0.54 | |
| Any reflux | 50 | 1.7 (2.2) | 9 | 3.1 (3.9) | 0.14 | |
| Deep vein reflux | 49 | 1.8 (2.2) | 10 | 2.8 (3.8) | 0.24 | |
| Superficial vein reflux | 26 | 1.9 (2.1) | 31 | 1.9 (2.9) | 0.98 | |
| IF Segment Sub-Score | 1 Month | |||||
| CFV compressible | 225 | 0.5 (1.5) | 58 | 1.1 (1.5) | 0.15 | |
| FV/PV compressible | 99 | 0.8 (1.7) | 187 | 0.6 (1.5) | 0.34 | |
| 12 Months | ||||||
| CFV compressible | 54 | 0.4 (1.3) | 8 | 0.5 (0.5) | 0.62 | |
| FV/PV compressible | 28 | 0.9 (1.7) | 34 | 0.1(0.3) | 0.07 | |
| Any reflux | 50 | 0.4 (1.0) | 9 | 1.0 (2.4) | 0.21 | |
| Deep vein reflux | 49 | 0.4 (1.0) | 10 | 0.9 (2.3) | 0.27 | |
| Superficial vein reflux | 26 | 0.3 (1.0) | 31 | 0.6 (1.5) | 0.44 | |
| FP Segment Sub-Score | 1 Month | |||||
| CFV compressible | 225 | 1.9 (2.7) | 58 | 2.2 (3.1) | 0.54 | |
| FV/PV compressible | 99 | 1.3 (2.2) | 187 | 2.3 (2.9) | 0.006 | |
| 12 Months | ||||||
| CFV compressible | 54 | 1.5 (2.0) | 8 | 1.3 (1.4) | 0.84 | |
| FV/PV compressible | 28 | 0.9 (1.6) | 34 | 2.0 (2.0) | 0.03 | |
| Any reflux | 50 | 1.4 (1.9) | 9 | 2.2 (2.1) | 0.28 | |
| Deep vein reflux | 49 | 1.5 (1.9) | 10 | 2.0 (2.1) | 0.44 | |
| Superficial vein reflux | 26 | 1.6 (2.1) | 31 | 1.4 (1.9) | 0.65 | |
Marder scores
p-values are adjusted for the baseline CFV and FV/PV compressibility for 1 and 12 months.
CFV=Common Femoral Vein, FV=Femoral Vein, PCDT=Pharmacomechanical Catheter-Directed Thrombolysis, PV=Popliteal Vein, SD=Standard Deviation, IF = Iliofemoral, FP = Isolated Femoral Popliteal, PTS=post-thrombotic syndrome
Relationship of Immediate Post-PCDT Residual Thrombus to Clinical Outcomes
For the overall study population, the post-PCDT thrombus score did not exhibit a statistically significant correlation with the 24-month mean Villalta, VCSS, or VEINES-QOL scores (Figure 3). PCDT Arm patients who developed PTS did not have more end-of-procedure residual thrombus than those who did not develop PTS (mean total thrombus score 2.7 points ± 3.3 versus 2.7 points ± 3.9, p = 0.95). PTS developed in 46% of patients with complete thrombolysis, in 47% of patients with minor residual thrombus , and in 53% of patients with substantial residual thrombus . Moderate-or-severe PTS developed in 13% of patients with complete thrombolysis, in 21% of patients with minor residual thrombus, and in 25% of patients with substantial residual thrombus (Figure 4).
Figure 3 -. Association of Post-PCDT Residual Thrombus and 24 Month Clinical Outcomes.
Analysis of covariance (ANCOVA) for association of post-PCDT residual thrombus (modified Marder score) with baseline-adjusted 24-month Villalta, VCSS, and VEINES-QOL scores in the following groups of PCDT recipients: (A) overall proximal DVT population; (B) iliofemoral DVT subgroup; and (C) femoral-popliteal DVT subgroup.
Figure 4 -. Proportion with Any and Moderate-or-Severe PTS by Post-PCDT Thrombus Score.
Bar graphs depicting the occurrence of any PTS and moderate-or-severe PTS in patients who had complete thrombolysis (post-PCDT total thrombus score 0), mild residual thrombus (post-PCDT total thrombus score between 0 and 6), and substantial residual thrombus (post-PCDT total thrombus score > 6). Differences between the groups were evaluated using chi square tests. Pairwise comparisons were examined using a Tukey post-hoc adjustment if the overall F test was significant. Results are presented for three groups of PCDT recipients: (A) overall proximal DVT population; (B) iliofemoral DVT subgroup; and (C) femoral-popliteal DVT subgroup.
For the femoral-popliteal DVT subgroup, the findings were similar, with no statistically significant relationships between the amount of immediate post-PCDT residual thrombus and either the 1-month clinical outcomes (leg pain, Villalta score, venous QOL score) (Table 5) or the 24-month clinical outcomes (scores on PTS severity and venous QOL scales) (Figure 3).
Table 5.
One-Month Clinical Outcomes by Post-PCDT Total Thrombus Score Categories
| 1 Month Outcome | Post-PCDT Total Thrombus Score* | All Proximal DVT Patients | p-value | IFDVT Subgroup | p-value^ | FPDVT Subgroup | p-value | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Leg Pain, Likert Scale, Adjusted mean, Std Err | 0 | 2.1 | (0.1) | 0.23 | 1.7 | (0.2) | 0.04 | 2.5 | (0.2) | 0.42 |
| 1 to 5 | 2.1 | (0.1) | 2.1 | (0.1) | 2.2 | (0.2) | ||||
| 6+ | 2.5 | (0.2) | 2.4 | (0.2) | 2.7 | (0.5) | ||||
| Villalta score, Adjusted mean, Std Err | 0 | 4.3 | (0.4) | 0.21 | 3.1 | (0.5) | 0.02 | 5.7 | (0.8) | 0.45 |
| 1 to 5 | 4.4 | (0.3) | 4.1 | (0.4) | 4.8 | (0.6) | ||||
| 6+ | 5.6 | (0.7) | 5.4 | (0.7) | 6.6 | (1.6) | ||||
| VEINES-QOL, Adjusted mean, Std Err | 0 | 66.1 | (2.3) | 0.11 | 71.1 | (2.8) | 0.02 | 59.6 | (3.8) | 0.11 |
| 1 to 5 | 65.8 | (1.7) | 63.9 | (2.0) | 68.5 | (2.9) | ||||
| 6+ | 58.3 | (3.4) | 58.5 | (3.7) | 57.6 | (7.7) | ||||
Leg Pain Severity (0 vs 6+, p=0.01), Villalta scores (0 vs 6+, p=0.007), and VEINES QOL (0 vs 6+, p=0.007; 0 vs 1 to 5, p=0.04)
Marder score on immediate-post-PCDT venogram
PCDT = pharmacomechanical catheter-directed thrombolysis; DVT = deep vein thrombosis; IFDVT = iliofemoral deep vein thrombosis; FPDVT = femoral-popliteal deep vein thrombosis
For the iliofemoral DVT subgroup, patients with higher immediate-post-PCDT total thrombus scores had higher (worse) 24-month Villalta scores (p=0.0098). Specifically, iliofemoral DVT patients with immediate-post-PCDT scores of 0 were found to have lower (better) Villalta scores at 24 months than those with immediate-post-PCDT scores of 1-5 (p=0.02) and > 6 (p=0.005). Lower (worse), yet non-significant, VEINES-QOL scores were observed with increasing post-PCDT thrombus score categories (p=0.08) (Figure 3). PTS developed in 44% of iliofemoral DVT patients with complete thrombolysis, in 49% of patients with minor residual thrombus, and in 48% of patients with substantial residual thrombus. Moderate-or-severe PTS developed in 8% of iliofemoral patients with complete thrombolysis and in 19% of patients with either minor or substantial residual thrombus (Figure 4). Patients with less immediate post-PCDT residual thrombus appeared to have less pain (p=0.04), lower Villalta scores (p=0.02), and higher venous disease-specific QOL scores (p=0.02) at 1 month, but these differences did not reach statistical significance (Table 5).
Discussion
In ATTRACT, PCDT facilitated substantial thrombus removal and venous flow restoration. However, in the overall proximal DVT population, the immediate-post-PCDT thrombus volume did not correlate with subsequent clinical outcomes or valvular reflux. In the iliofemoral DVT subgroup alone, a lower volume of immediate-post-PCDT residual thrombus was not associated with less frequent PTS but was associated with reduced 24-month PTS severity and possibly also with better 1-month symptom status and venous QOL over 1 month and 24 months.
Thrombus removal with PCDT in ATTRACT was comparable to previous large prospective studies that reported independent core laboratory assessment of venograms after infusion CDT. In a urokinase CDT registry, Grade I (< 50%), II (50-99%), or III (100%) lysis was seen in 13%, 52%, and 34% of patients, respectively, equating to residual thrombus of at least 9% (weighted mean) of the vein volume (15). In the CAVENT randomized trial, mean residual thrombus of 9% of the vein volume (1.3 points on 14-point scale) was seen after CDT (16). In ATTRACT, the core laboratory readers found 84% of patients to have ≥ 50% thrombus removal; residual thrombus occupied 11% of the vein volume post-PCDT (2.7 points on 24-point scale) (5).
Based largely on operator-reported findings, SIR guidelines suggest that ≥ 80% of CDT-treated patients should have > 50% thrombus removal or restoration of iliofemoral venous patency (17). In ATTRACT, 96% of PCDT-treated patients were reported by the operators to have ≥ 50% thrombus removal, and 99% had iliofemoral venous patency at procedure end. Hence, the immediate post-procedure results in ATTRACT met or exceeded SIR performance thresholds.
Correlations in Overall Proximal DVT Study Population:
In the study’s PCDT Arm, strong relationships between immediate-post-PCDT residual thrombus volume and clinical outcomes were not identified. Specifically, PCDT Arm patients who developed PTS over 2 years did not have more end-of-procedure thrombus than PCDT Arm patients who did not develop PTS and even in patients with complete lysis, 46% developed PTS and 13% developed moderate-or-severe PTS. These findings are similar to those of the CAVENT Trial. In that study (3,4,16), the immediate-post-PCDT residual thrombus score in the CDT Arm did not correlate with development of PTS or with the continuous Villalta score over 24 months either.
Correlations in Iliofemoral DVT and Femoral-Popliteal DVT:
In patients with DVT limited to the femoral and popliteal veins, significant correlations were not observed between the immediate-post-PCDT residual thrombus score and clinical outcomes. In contrast, in patients with iliofemoral DVT, a lower volume of immediate-post-PCDT residual thrombus correlated with reduced PTS severity over 2 years, and moderate-or-severe PTS developed in only 8% of iliofemoral DVT patients who had complete lysis. Associations with less severe leg pain, lower Villalta score, and better venous QOL at 1 month follow-up and with better venous disease-specific QOL at 24 months were highly suggestive but did not reach statistical significance.
This study’s findings leave open the possibility that the open vein hypothesis may not be valid, or that it requires substantial modification. Clearly, the pathophysiology of PTS remains poorly understood – in addition to potentially impairing the venous flow conduit, DVT-related venous/peri-venous inflammation may exert myriad biological effects upon the vein wall and valves. Given that PCDT provided robust thrombus removal and venous patency restoration in this study, why did it fail to demonstrate a much larger effect on long-term clinical outcomes?
In contrast with most previous studies, strengths of ATTRACT include its size, randomized design, performance of PCDT by a large number of credentialed physician operators, standardized assessor-blinded outcome assessment using validated instruments, venogram assessment by physician operators and independent readers, and overall methodological rigor.
On the other hand, operator assessments of venous flow were not independently adjudicated and did not address dynamic flow characteristics, nor was venous patency assessed by venography during follow-up. The operators did not routinely utilize intravascular ultrasound (IVUS), which may be more sensitive than venography for evaluating residual thrombus and stenosis (18). However, during this study, IVUS was not an established element of standard practice for acute DVT therapy, and there are no well-validated IVUS scoring systems for venous thrombus. It has been speculated that PCDT outcomes could have been improved by more frequent, or less frequent, stent placement (19). Although venographically occult disease could have been missed in some patients, the small volume of post-PCDT residual iliofemoral thrombus and the near-universal iliofemoral venous patency restoration do not support the notion that a “failure to stent” influenced the study’s outcome or that additional intervention would have justified the risks.
The Marder score is a well-validated tool that enables an overall assessment of the quantity of thrombus in lower extremity and iliac vein segments. However, it does not provide information on the position of the thrombus (e.g., mural versus central) and its potential to limit venous flow.
Was PCDT in ATTRACT simply performed too late to prevent irreversible venous injury? Although in this analysis, patients randomized within 7 days after symptom onset may have had slightly greater thrombus removal, it was previously reported that symptom duration < 7 days did not influence the effect of PCDT upon the occurrence of PTS or moderate-or-severe PTS (5,7).
It is possible that differences between CDT and PCDT are relevant to long-term patient outcome. Among the CAVENT, CAVA, and ATTRACT Trials, only CAVENT observed an effect on PTS prevention (3). Unlike PCDT in ATTRACT, CDT in CAVENT did reduce valvular reflux (20). It remains possible that the safety/efficiency advantages of PCDT (relative to CDT) are offset by less complete restoration of inflow from axial (below-knee popliteal) or non-axial (tibial, profunda femoral) veins due to the reduced rt-PA exposure, or that the mechanical action of thrombectomy devices causes macroscopic or microscopic injury to the vein wall or valves. It is possible that routine use of tibial vein access, newer thrombectomy devices (if effective and atraumatic), or IVUS could reduce the amount/impact of residual femoral-popliteal thrombus.
Another potential explanation for the ineffectiveness of PCDT in preventing PTS is that the initial technical result was undermined by new thrombus deposition (perhaps with accompanying inflammation) over time. This is supported by the lack of correlation between immediate thrombus removal and ultrasound findings at 1 and 12 months. Despite the high degree of thrombus removal by PCDT, approximately 20% of common femoral, 50% of femoral, and 60% of popliteal veins were incompletely compressible at 1 month (8). Similarly, in the urokinase CDT registry, the 1-year primary patency was just 60% (19). In CAVENT, at 6 months, only 66% of CDT-treated patients had patent veins and just 29% were free of residual thrombus and valvular reflux (16,20). Neither CAVENT nor ATTRACT saw a correlation between the status of the immediate-post-thrombolysis venogram and 2-year PTS in CDT/PCDT-treated patients. However, in CAVENT, 6- and 24-month iliofemoral venous patency did correlate with PTS and in ATTRACT, CFV non-compressibility at 1 month correlated with more PTS, more moderate-or-severe PTS, and worse venous disease-specific QOL over 24 months (p < 0.01) (8,16,20).
Hence, subclinical thrombus formation during the early weeks after CDT/PCDT may be more frequent than previously appreciated, and may undermine the long-term results of therapy. Additional study of the optimal anti-thrombotic strategy after CDT/PCDT is therefore warranted. It seems possible that the “open vein hypothesis” mainly applies to the iliofemoral venous outflow segment, or that it only applies when patency is durably maintained. Future studies may benefit from objective scoring/assessment of dynamic venous flow and from serial imaging surveillance to confirm the degree to which patency is maintained over time.
The ATTRACT Trial demonstrated positive effects of PCDT upon leg symptoms, PTS severity, and venous QOL in patients with acute iliofemoral DVT (7). The current analysis supports the notion that when PCDT is used to treat acute iliofemoral DVT, the degree of benefit achieved will be enhanced by clinician attention to maximizing thrombus removal and ensuring effective anti-thrombotic therapy post-procedure. However, clinicians should not suggest to patients that thrombus removal will prevent PTS, and use of PCDT for femoral-popliteal DVT should be rare.
Additional Limitations:
This analysis involved substantial multiple statistical testing. The sample size limited analyses of subgroups and, in particular, the 1-year ultrasound outcomes. Because this analysis was limited to the PCDT Arm, with data skewing heavily towards very low post-PCDT thrombus scores, its applicability to non-PCDT-treated patients is unknown.
Conclusion
PCDT in ATTRACT was highly effective in removing venous thrombus and in restoring flow in patients with acute proximal DVT. However, the occurrence of PTS over 2 years did not parallel the degree of initial thrombus clearance. In patients with iliofemoral DVT, reduced immediate-post-PCDT thrombus burden correlated with reduced 2-year PTS severity and possibly also with better 1-month symptom status and better QOL. Future study of the open vein hypothesis should focus on iliofemoral DVT, with particular attention to how patency can be maintained over time. Other mechanisms of PTS pathogenesis also warrant investigation to reduce the burden of PTS.
Supplementary Material
CONSORT 2010 checklist of information to include when reporting a randomised trial*
| Section/Topic | Item No | Checklist item | Reported on page No |
|---|---|---|---|
| Title and abstract | |||
| 1a | Identification as a randomised trial in the title | 1 |
|
| 1b | Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) | 2 |
|
| Introduction | |||
| Background and objectives | 2a | Scientific background and explanation of rationale | 3 |
| 2b | Specific objectives or hypotheses | 3 |
|
| Methods | |||
| Trial design | 3a | Description of trial design (such as parallel, factorial) including allocation ratio | 4 |
| 3b | Important changes to methods after trial commencement (such as eligibility criteria), with reasons | NA |
|
| Participants | 4a | Eligibility criteria for participants | 4 |
| 4b | Settings and locations where the data were collected | 4 |
|
| Interventions | 5 | The interventions for each group with sufficient details to allow replication, including how and when they were actually administered | 5-6 |
| Outcomes | 6a | Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed | 5-7 |
| 6b | Any changes to trial outcomes after the trial commenced, with reasons | NA |
|
| Sample size | 7a | How sample size was determined | Prev Report |
| 7b | When applicable, explanation of any interim analyses and stopping guidelines | NA |
|
| Randomisation: | |||
| Sequence generation | 8a | Method used to generate the random allocation sequence | Prev Report |
| 8b | Type of randomisation; details of any restriction (such as blocking and block size) | Prev Report |
|
| Allocation concealment mechanism | 9 | Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned | Prev Report |
| Implementation | 10 | Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions | Prev Report |
| Blinding | 11a | If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how | 6 |
| 11b | If relevant, description of the similarity of interventions | NA |
|
| Statistical methods | 12a | Statistical methods used to compare groups for primary and secondary outcomes | 7,8 |
| 12b | Methods for additional analyses, such as subgroup analyses and adjusted analyses | 7,8 |
|
| Results | |||
| Participant flow (a diagram is strongly recommended) | 13a | For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome | 9 |
| 13b | For each group, losses and exclusions after randomisation, together with reasons | 9 |
|
| Recruitment | 14a | Dates defining the periods of recruitment and follow-up | Prev Report |
| 14b | Why the trial ended or was stopped | NA |
|
| Baseline data | 15 | A table showing baseline demographic and clinical characteristics for each group |
Table 1 |
| Numbers analysed | 16 | For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups | 7-9, 9-12, Tables |
| Outcomes and estimation | 17a | For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) | 9-12, Tables |
| 17b | For binary outcomes, presentation of both absolute and relative effect sizes is recommended | 9-12, Tables |
|
| Ancillary analyses | 18 | Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory | 9-12, Figures, Tables |
| Harms | 19 | All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) | NA |
| Discussion | |||
| Limitations | 20 | Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses | 15-17 |
| Generalisability | 21 | Generalisability (external validity, applicability) of the trial findings | 15-17 |
| Interpretation | 22 | Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence | 15-17 |
| Other information | |||
| Registration | 23 | Registration number and name of trial registry | Title Page |
| Protocol | 24 | Where the full trial protocol can be accessed, if available | Title Page |
| Funding | 25 | Sources of funding and other support (such as supply of drugs), role of funders | Title Page |
We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.
Acknowledgements:
The authors wish to thank Dr. Andrei Kindzelski (NHLBI Project Officer) and the entire network of investigators and study staff at the ATTRACT Trial coordinating centers, core laboratories, vascular ultrasound laboratories, and clinical centers (see Appendix).
Sources of Study Funding and In-Kind Support:
The ATTRACT Trial was supported by grants from the National Heart, Lung, and Blood Institute (NHLBI) for the clinical coordinating center (U01-HL088476 to Washington University in St. Louis) and data coordinating center (U01-HL088118 to McMaster University, Hamilton, ON); the Washington University Center for Translational Therapies in Thrombosis, which was supported by a grant from the NHLBI (U54-HL112303); the Washington University Institute of Clinical and Translational Sciences, which was supported by a grant from the National Center for the Advancement of Translational Sciences (UL1-TR00044810); Boston Scientific; Covidien (now Medtronic); Genentech; the Society of Interventional Radiology Foundation; the Canada Research Chairs Program (Tier 1 support to Dr. Susan Kahn); the CanVECTOR Network (funded by Canadian Institutes of Health Research CDT-142654, to Dr. Kahn); the Heart and Stroke Foundation of Canada (Investigator Award to Dr. Kearon); and a Jack Hirsh Professorship in Thrombosis (to Dr. Kearon). BSN Medical donated the compression stockings.
Footnotes
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Disclosures:
Mahmood K. Razavi: Personal fees Abbott Vascular, Medtronic, Boston Scientific, Phillips, and Terumo, outside the submitted work.
Amber Salter: Nothing to disclose.
Samuel Z. Goldhaber: Grants from Bayer, Boehringer-Ingelheim, BMS, BTG EKOS, Daiichi, Janssen, The Thrombosis Research Institute. Personal fees from Bayer and Boehringer-Ingelheim, outside the submitted work.
Samantha Lancia: Nothing to disclose.
Susan R. Kahn: Nothing to disclose.
Ido Weinberg: Personal fees from Novate Medical and Magneto Atherectomy Solutions.
Clive Kearon: Nothing to disclose.
Ezana M. Azene: Nothing to disclose.
Nilesh H. Patel: Nothing to disclose.
Suresh Vedantham: Grants from Cook Medical and Medi USA.
Trial Registration
This study is registered at www.clinicaltrials.gov (NCT007095).
Study Protocol
The full protocol can be accessed by e-mailing Dr. Suresh Vedantham: vedanthams@wustl.edu
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