Abstract
In 2017, the long awaited results of the ATTRACT trial were published in the New England Journal of Medicine leaving the scientific community with disappointment as the study did not show the expected results. Producing not the expected outcome is not uncommon in science – furthermore, it is important to disapprove common beliefs. But has the ATTRACT trial really the power to change our practice? Are the results correct in terms of evidence based on the methods used?
In 2017, the long awaited results of the ATTRACT trial were published in the New England Journal of Medicine1,2 leaving the scientific community with disappointment as the study did not show the expected results. Producing not the expected outcome is not uncommon in science – furthermore, it is important to disapprove common beliefs. But has the ATTRACT trial really the power to change our practice? Are the results correct in terms of evidence based on the methods used? To understand the results, it is important to analyze the methods of the trial and to discuss them in a broader view.
What is the ATTRACT trial?
Post-thrombotic syndrome (PTS) is a frequent (20–50%) late complication after deep vein thrombosis (DVT). PTS is a feared complication as it poses a significant risk to reduce quality of life for the patient and increases health-care cost of these patients significantly.3,4 In recent years, catheter directed thrombolysis (CDT) has shown promising initial results5,6 by reducing the clot burden in the thrombosed veins.
Therefore, the overall goal of the ATTRACT trial was to reduce PTS in patients with DVT by direct lysis in the occluded vessel. The ATTRACT trial (Acute venous thrombosis: thrombus removal with adjunctive catheter-directed thrombolysis) (clinicaltrials.gov NCT00790335) was a multicenter prospective randomized controlled trial to assess the effect of CDT on the incidence of PTS in patients with symptomatic proximal DVT in comparison to standard care.
692 patients with symptomatic proximal DVT were randomized in 56 clinical centers. Patients had DVT in the femoral, common femoral or iliac vein. Patients undergoing standard of care got anticoagulation therapy according to current guidelines and additionally compression stockings, while the other group of patients received pharmacomechenical CDT using recombinant tissue plasminogen activator (rt-PA) additionally to standard care. Villalta score >5 or leg ulcer was seen as primary outcome between 6 and 24 month after DVT treatment.
Contradictory to the expectation that CDT should produce better results with less PTS, this hypothesis could not be proven by the study. In the post-procedural time period up to 24 months, no statistical significant difference of patients with PTS was found. On the other hand, the authors described an increase in major bleeding complications in the patient group undergoing CDT. Besides the results were only slightly significant, this is a major finding that needs to be discussed, because if a new methods poses a significant increased risk to the patients why should it be applied, while the positive outcome measures are not better?
On the other hand, the severity score of PTS score was lower in the CDT group, while overall quality of life did not differ between both groups.
How to interpret the results
It has been disappointing to read the results, as the community expected the CDT group to deliver much better results. Was it false expectation or may methodological difficulties have produced these results?
One of the major challenges of the trial was the inclusion of a sufficient number of patients. In order to achieve the number of 692 patients, over 27 000 patients had to be screened. This illustrates inclusion difficulties and raises questions about representative study results. Furthermore, the 692 patients were randomized in 2 groups in 56 centers. As 336 patients entered the CDT arm of the study, this would result in just 6 interventions per center raising concerns about the individual experience on CDT treatment in the involved centers.
The list of exclusion criteria is pretty long, while in terms of inclusion a wide mix of different anatomical segments with DVT were included (e.g. iliac and peripheral DVT). This again makes interpretation of results difficult and leads to an increase heterogeneity of input data – as well as output data. Previous registries already showed a higher benefit of treating iliofemoral thrombosis rather than femoropopliteal thrombosis,7 therefore it remains unclear why the study design focused on a broad spectrum of DVT.
One of the major advantages of CDT is the possibility to treat underlying pathologies (e.g. May Thurner syndrome). It is not clear if there was a dedicated strategy in the trial to deal with underlying disease. The number of stents is given, but it is not exactly clear how different pathologies were approached, as well as a wide variety of stents were used that were not dedicated venous stents. Furthermore, it remains unclear how the amount of thrombus removal adds to the results (76% thrombus removal), as it is known that the amount of thrombus removal directly correlates with morbidity.8 It remains unclear how short-term access was evaluated, it is common sense that short-term success also needs to be evaluated in patients undergoing CDT.
Finally, there is a lack of imaging prior to the treatment and after the intervention. Previous studies have extensively used at least ultrasound, while more and more studies have facilitated, e.g. MR venography, CT venography pre-interventionally and during intervention intravenous ultrasound to better visualize pathologies and treatment success.9
Perspective in 2020
Since ATTRACT was designed and published some years have passed. The results from the first venous registry, which were published in 19997 were promising. Previous trials using CDT such as the CAVENT trial5,6 (catheter-directed thrombolysis for DVT) had published 2 and 5 year results that were consistently better for CDT with regard to frequency of PTS (43% vs 71%). In the CAVENT trial patients were randomized between CDT vs standard therapy, while CDT was an add on to standard therapy. The number needed to treat was only 4 after 5 years. However, similar to the ATTRACT trial the study could not show a difference in the quality of life after 5 years. The TORPEDO10 trial which was published in 2012 was one of the first studies to demonstrate superior results of endovascular treatment of DVT in comparison to standard treatment. In this randomized trial, 183 patients were randomized. The results showed significant lower rates of recurrent DVT in the patient treated by endovenous interventions. Current publications such as the ACCESS PTS study10 did show an increase in quality of life after 1-year using ultrasound accelerated CDT, but this study has no RCT trial design. Quality of life as a measure of success has been criticized for a long time. The so-called hedonistic treadmill which refers to the question how much influence a pathology has on the quality of life in general – meaning that the influence of PTS on quality of life could be overestimated.
Did recent developments overcome the shortcomings of the trial? It is not easy to say. Criticism of the ATTRACT trial has shown the shortcomings of the trial design, but to date no other large RCT trial has demonstrated
In the recent ACCESS PTS study11 which focusses on ultrasound accelerated CDT which was published in 2020 the use of CDT resulted after short term follow-up after 1 year in an increase in quality of life. Although it has to be said that this study is not a prospective randomized controlled trial. Two recent publications on the CAVA trial using ultrasound-accelerated CDT also produced contradictory results, claiming that optimal patient selection is necessary to gain optimal results.12,13
What to conclude
The ATTRACT trial has certainly messed up the ideas of the scientific community on the benefit of CDT. The shortcomings of the study design unfortunately have raised more questions. Besides smaller studies and the CAVENT trial larger studies are still lacking. It seems that proper imaging, patient selection and treatment with newest devices can reduce the clot burden and produce a reduction in PTS as well as improvement of quality of life. It is desirable to reproduce these results in a larger - ideally RCT - trial.
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