Speaking at the annual meeting of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE 2019; 7–11 September, Barcelona, Spain), Stephen Black (Guys and St Thomas’ Hospital, London, UK) emphasised that “ATTRACT and CAVA are not the end of our treatment; instead, they are the beginning of a road to prove which patients will benefit most from treatment”. He added that more data is needed following the ATTRACT trial, which concluded that catheter-directed thrombolysis does not reduce the risk of post-thrombotic syndrome (PTS) in lower extremity DVT patients.
The hot topic symposium session—which asked the question “Does ATTRACT change our DVT management practice?”—addressed criticism of the ATTRACT trial and considered what the future might hold for deep vein thrombosis (DVT) interventions. As part of the session, Wael Saad (Washington University, St Louis, USA), Gerard O’Sullivan (Galway University Hospital, Galway, Ireland) and Rick de Graaf (Clinic of Friedrichshafen, Friedrichshafen, Germany) gave an overview of the study, explaining why its findings alone will not have a significant impact on practice.
ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-directed Thrombolysis), as described by investigator Saad, was “a multi-centre, randomised, open-label and assessor-blinded phase three trial with two limbs; the control standard of care, which was anticoagulation and compression stockings (30–40mmHg), and the pharmaco-mechanical group—anticoagulation and compression stockings in addition to catheter-directed therapy”. Furthermore, the development of PTS (Villalta score ≥ 5), or an ulcer on the ipsilateral leg, anytime between six and 24 months was established as the primary outcome.
Results of the trial showed that there was no significant difference between the two treatment groups in terms of primary outcomes, with 47% of patients in the CDT plus anticoagulation cohort developing PTS between six and 24 months, compared to 48% in the control group. Moreover, there was no difference in safety outcomes between the two groups. Of the trial’s conclusion, Saad said: “The addition of pharmaco-mechanical catheter directed fibrinolysis in symptomatic patients with proximal lower extremity DVT did not reduce the risk of PTS.”
Problems with the ATTRACT trial
In his review of the study, Saad underlined that there was a “considerable” amount of missing assessment, with 80 patients (two thirds of which were in the control group) not providing any data. In addition to this, a large number of patients were excluded by the criteria of the trial, including those suspected of non-compliance with protocol. Saad also revealed that investigators “encountered a lot of patients who initially enrolled but, when they found out they would receive anticoagulation alone, withdrew from the study”.
Following Saab’s presentation, O’Sullivan also drew attention to “flawed recruitment” as a shortcoming of the study, highlighting that only one in 50 patients (692 in total out of 27,000) made the cut for ATTRACT. “It is not generalisable to real-life, day-to-day practice,” he said, agreeing with Saab that while it is normal for trials to reject a proportion of patients, 98% is far more than usual. On the other hand, a decision to include femoro-popliteal DVT patients to try and increase recruitment resulted in the de-powering of the iliofemoral arm, preventing any “statistically significant” results from being found.
Another problem with the study was the use of the Villalta scale which, as O’Sullivan asserted, “has never been published or subjected to the level of statistical analysis one would expect for a scale that is so widely used”. Although it is considered a useful tool for long-term patient follow-up, Villalta is heavily weighted towards swelling, skin changes and ulceration, failing to account for venous claudication and other aspects such as weight gain. “Venous claudication and weight gain are the two most common problems my patients have after one year, but there is no mention of them in Villalta” added O’Sullivan.
Beyond issues with recruitment and classification, the lack of dedicated imaging was also a drawback to the trial, as there was no magnetic resonance venography (MRV) scan before operation, no intravascular ultrasound (IVUS) during operation, and no ultrasound mandated following operation, despite this being a routine procedure in any European centre. The lack of dedicated venous kit, including venous dedicated stents, was noted too by O’Sullivan as a problem with the trial.
Has ATTRACT impacted practice?
Presenting on whether or not the findings of the ATTRACT trial have had any significant effect on his practice, de Graaf stated that before the study he treated patients with iliofemoral DVT, using an MRV to select the uncomplicated fresh clot, stenting the underlying cause as opposed to residual thrombosis, and removing as much of the thrombus as reasonably possible. He also drew attention to other literature, emphasising that “the more thrombus you take out, the less likely it is for the patient to develop PTS,” as well as findings from the European Journal of Vascular and Endovascular Surgery (EJVES) that show removing as much thrombus as possible reduces the chances of recurrent DVT.
Although the ATTRACT trial offered a different conclusion, suggesting that DVT should not be managed with endovascular treatment at all, de Graaf described this option as unrealistic, affirming that iliofemoral DVT with less than 14 days of symptoms should be treated. Like Saad and O’Sullivan, he also highlighted key areas of criticism such as “insufficient stenting”—which can lead to many obstructions being missed—and “inadequate evaluation of thrombus removal”; according to de Graaf, “angiography is not good enough,” with IVUS representing a better imaging option.
The future of the practice
With a level of consensus established amongst the presenters regarding the potential impact, or lack thereof, of the ATTRACT trial, focus also turned to the lessons that can be learned from the failure to achieve successful results. “We have to focus on technical success,” argued Black, who added: “When you look into the supplementary tables, ATTRACT was only successful in 60% of patients who were treated. If you have only 60% of technical success, it is not surprising that there is no difference in outcome.”
In order for future trials in the space to achieve higher levels of technical success, Black underlined a number of key areas for investigators to take note of, explaining that attention to detail is absolutely crucial for a better standard of results. “This means really rigorous anticoagulation strategies,” he said, “making sure the patient is fully anticoagulated when they have finished the procedure”.
Other adjuncts to standard of care, such as intermittent pneumatic compression (IPC) and the use of stockings, need to be monitored carefully, as well as strictly conducted follow-up and surveillance. In addition to this, Black commented that “in all of these studies, if the vein was open the patient did better, so the whole point is that open vein equals good results of patients”.
The future of trials in this space, according to Black, will also be affected by the introduction of new, mechanical devices, prompting a movement away from catheter-directed therapy to safer treatment, lowering the bleeding risk of patients by “reducing dependence on lytic”. Patient-centre outcome measures are also important, with a replacement for Villalta needed that takes the needs of the individual patient into account.
Black also provided a cost-effectiveness analysis, and stated: “With this data, and based on UK results, treating patients is still cost-beneficial and may even be dominant over not treating them despite the bad outcomes we saw in ATTRACT. This means that if we get better at outcomes and make the procedures safer, we are going to get a very cost-effective treatment for our patients and this is principally because you reduce the rate of moderate and severe PTS.”
Furthermore, Black concluded: “Better selection and outcome measures are needed, we need to commit to registries first and then run further trials—which is absolutely needed if we are going to influence the payers and other bodies which allow us to continue to perform interventions—and there will be new devices in the future that will change our patient treatment.”