ATTRACT results are “a springboard” for future pharmacomechanical thrombolysis research

Images courtesy of Michael Lichtenberg

Data from the randomised controlled ATTRACT trial revealed that the addition of catheter-based intervention to standard-of-care anticoagulation failed to significantly decrease the occurrence of post-thrombotic syndrome in patients who received this treatment strategy when compared with its occurrence in patients who received anticoagulation alone. 

While full results are still awaiting publication, headline data were presented at the Society for Interventional Radiology annual meeting (17–22 March, Washington, DC, USA) by Suresh Vedantham, the national principal investigator of the trial and professor of Radiology and Surgery, Mallinckrodt Institute of Radiology, Washington University School of Medicine in St Louis, USA.

Short-term data captured from the trial showed that the effects of pharmacomechanical catheter-directed thrombolysis (PCDT) resulted in more major bleeds in the interventional arm (1.7%) than in the in the control arm (0.3%; p=0.049). There were also significantly more instances of any bleeding (4.5%) in the interventional arm than in the control arm (1.7%, p=0.049). There were no fatal or intracranial bleeds in either arm of the trial indicating that few patients will be harmed as a result of thrombolytic therapy.

For long-term effects of PCDT, the data showed that 46.7% of the group that received interventional therapy went on to develop post-thrombotic syndrome, whilst 48.2% of those who received anticoagulation alone went on to develop post-thrombotic syndrome (p=0.56).

While there has been a certain amount of disappointment at the headline findings of this landmark trial, experts have called the data both “illuminating” and “hypothesis-generating”. Venous News spoke to a selection of experts about their reactions to the initial data, what impact they think it may have on practice, and what future research projects should now focus on.

 Initial data 

Reaction to the initial data has stressed the importance of the full dataset, which has not yet been published. As Michael Jaff (Boston, USA) explains, “I do not think anyone can interpret the results of ATTRACT based on a brief and limited presentation at a national meeting. We must resist the temptation to draw conclusions until we review the entire dataset in a peer-reviewed journal, and I would urge my colleagues to follow this advice.”

That said, Rick De Graaf (Maastricht, The Netherlands) was not surprised by the data. “Although it has been obvious for quite some time now that iliofemoral deep vein thrombosis is more significant in the development of post-thrombotic syndrome in comparison to femoropopliteal deep vein thrombosis, still both groups were included in the study,” he explained. “For sure, the femoropopliteal group diluted the impact of thrombus removal in post-thrombotic syndrome development. I have never treated an isolated femoral deep vein thrombosis by PCDT before, and I do not know physicians that advocate this treatment. Therefore, the currently available study data do not encourage me to change current treatment strategies.”

For Michael Lichtenberg (Arnsberg, Germany), “it can now be clearly seen that only patients with iliac vein thrombosis will benefit from clot removal therapy. As Surest Vedantham subgroup of patients with iliofemoral deep vein thrombosis, not every patient benefits from PCDT in terms of post-thrombotic syndrome. The next step should be to interpret the full data set of the study and try to find out if there are predictors which give us support for the best indication and patient circumstances.”

Previous studies have been “convincing” in reporting that the percentage of residual thrombus relates to post-thrombotic syndrome, according to De Graaf. He notes that although the rate of mean thrombus removal in ATTRACT was 74%, it is not yet clear how this was evaluated, ie. if intravascular ultrasound (IVUS) was used in all cases. “Without knowledge about the exact percentage of thrombus removal and thus the success of the intervention, definite conclusions cannot be drawn,” he explains. “I would like to know how patients with >90% thrombus removal performed. Furthermore, we know that in a fair number of deep vein thrombosis patients an underlying obstruction is present. Were all patients imaged accurately for this obstruction to be identified and were all significant lesions treated adequately? These data may also have an impact on the final message from this study.”

Practical impact 

The impact of these data, Jaff believes, will depend “on the perspective of the reader.” He continues, “For the interventionist who believes, in his/her heart of hearts, that there absolutely are patients who have improved from catheter-directed thrombolysis, their interpretation will be that for patients under age 65 with advanced acute symptoms, proximal iliofemoral deep vein thrombosis, and acceptably low bleeding risk, catheter-directed thrombolysis is the treatment of choice. However, for the strict clinical trialist who believes that the primary endpoint of a trial is really the beginning and end of the story, their interpretation will be that catheter-directed thrombolysis offers no real advantage over standard anticoagulation, and carries a statistically increased risk of haemorrhagic complications.”

Ramon Varcoe (Sydney, Australia), believes that the ATTRACT results will reduce the use of PCDT and other types of mechanical thrombolysis for proximal deep vein thrombosis. He elaborates, “Whilst the results have only just been released and we have not yet had the opportunity to drill down into the finer detail, it appears that the primary endpoint of post-thrombotic syndrome incidence at 24 months was not reduced by the addition of PCDT. This is a contentious area anyway, with many stakeholders already sceptical of the open vein hypothesis and reluctant to expose patients to invasive therapies and bleeding risk without convincing evidence of benefit. This result will only make those sceptics more resolute in their opposition.”

As for day-to-day approaches for the experts that spoke to Venous News, none plan to change their established practices based on the initial ATTRACT data. De Graaf and colleagues “are still including patients in our randomised deep vein thrombosis trial (CAVA study). In contrast to ATTRACT, we only include iliofemoral thrombosis. Hopefully, our data will reinforce the preliminary ATTRACT data that iliofemoral patients will benefit from percutaneous recanalisation.”

“In my view,” Varcoe says, “the trial results still support the use of PCDT in patients with severe symptoms of swelling and pain, and they suggest that incidence and severity of post-thrombotic syndrome is reduced in iliofemoral deep vein thrombosis at 24 months. I believe that both groups should continue to receive PCDT, at least until we have more detail from the trial to say otherwise. From what we have seen, however, patients with mild symptoms and femoropopliteal deep vein thrombosis can be treated with anti-coagulation and stockings alone. This is my current practice.”

Michael Lichtenberg agrees, explaining that “ATTRACT will not change our practice as it showed that patients with iliofemoral deep vein thrombosis benefit from a thrombectomy therapy.”

“On average, we perform two to three venous thrombectomy procedures per week. Based on the already existing literature and our experience, we only perform thrombectomy in patients with iliac vein thrombosis. Every indication is judged by a multidisciplinary team depending on patient age, bleeding complication and peri- and post-interventional complication rates. Ninety per cent of the patients we treat are younger than 45 years with a high risk for post-thrombotic syndrome. After effective thrombus removal, every iliac vein is analysed with an intravascular ultrasound technique to find an underlying pathology or persisting obstruction. Therefore, the stenting rate in our centre is quite high as we usually find an obstructive component. “

The future direction of research 

Although ATTRACT has failed to meet its primary endpoints, its results will offer a springboard for ongoing research in this area. As Jaff says, “I suspect that ATTRACT will launch a series of subsequent studies designed to identify optimal patient characteristics for specific therapies, including venous valve technologies to improve the ravages of post-thrombotic chronic venous insufficiency.”

Varcoe suggests that there “is a lot more to come from the ATTRACT trial. With time, we will begin to see results of the function of the valves that will help us to better understand post-thrombotic syndrome and the open vein hypothesis. We will also see the release of the all-important economic data around the use of PCDT and gain further insight into the quality-of-life impact of the disease with the two arms of treatment according to deep vein thrombosis types. I am also interested in seeing longer-term data around post-thrombotic syndrome incidence, as I suspect that over longer time-points we may observe a greater benefit in avoiding it with PCDT. This is what I have observed in my own clinical practice.”

“We need to interpret the stenting rate in this trial and also analyse the way patients were stented,” argues Lichtenberg. “How was a haemodynamic satisfying result defined? Even though this study was not powered to find differences between different pharmacomechanical catheter-directed thrombolysis techniques, we need to analyse if there is an impact of bad techniques.” Lichtenberg continues, “We need to analyse if a pure mechanical thrombectomy therapy is even more effective than pharmacomechanical and catheter

directed thrombolysis. Additional thrombolysis is usually not indicated, therefore bleeding complications are lower. Pharmacomechanical thrombectomy also gives the chance to finish the therapy during one endovascular approach; no follow-up angiographies are needed. Therefore, I believe that a multidisciplinary independent prospective study is needed to find answers to questions which occur at the beginning of the therapy.”

De Graaf believes that the most benefit from future research is to be expected in iliofemoral obstructions. “Above all,” he says, “future studies should make an effort to identify an underlying chronic obstruction in any deep vein thrombosis case, preferably with IVUS. Thereafter, we need to find out if the obvious treatment strategy with stent implantation can be substantiated by data. A huge mistake may be to forget completely about femoropopliteal deep vein thrombosis patients. Not recommending intervention for femoropopliteal patients does not mean that we do not have to look for a central venous obstruction as a cause for this peripheral deep vein thrombosis. The possible compression might still be significant in initial deep vein thrombosis occurrence and future recurrence. We need to find out if stenting a central outflow obstruction can prevent recurrence of femoropopliteal deep vein thrombosis with worsening towards an iliofemoral thrombosis.”