Lytic Therapy, Clot Removal in DVT Doesn't Prevent Postthrombotic Syndrome

Fran Lowry

December 07, 2017

ST LOUIS, MO — The risk of postthrombotic syndrome (PTS) didn't go down significantly after treatment of proximal deep vein thrombosis (DVT) via catheter, using thrombolytic agents and thrombectomy or other invasive device measures, in a randomized comparison with anticoagulation therapy alone[1].

In a study published in the December 7, 2017 issue of the New England Journal of Medicine, the proportion of patients receiving anticoagulation with vs without pharmacomechanical thrombolysis and who developed PTS over 24 months was 47% and 48%, respectively.

The more invasive treatment was associated with a higher risk of major bleeding.

"We were somewhat surprised by the findings," Dr Suresh Vedantham (Washington University, St Louis, MO), lead author on the report on the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial, told | Medscape Cardiology.

Postthrombotic syndrome, which can include chronic limb pain and swelling with possible later complications, occurs in about half of patients with proximal DVT despite use of standard blood-thinning drugs.

There is controversy about the value of pharmacomechanical catheter-directed thrombolysis, which in this trial entailed catheter delivery of tPA to the thrombus along with thrombus aspiration or maceration in patients with DVT, the authors note.

"There have been other preliminary studies that pointed in the direction that removing the clot may improve long-term outcomes," Vedantham said. And "many physicians who do the procedure have come to believe that it works, in terms of preventing longer-term problems. But to be fair, there has not been a large rigorous study to establish this belief with certainty," he said.

"It sounds very logical. If the clot is what is causing the long-term problems, and if you remove the clot, it may be likely to help. But clearly, there are other mechanisms at play here."

Although the trial was negative, "I don't know that it totally puts the nail in the coffin for an intervention for acute proximal DVT," Dr Natalie Evans (Cleveland Clinic Foundation, OH) told | Medscape Cardiology.

"I think probably in very carefully selected patients, for instance in a young patient with a very extensive high proximal DVT who is very symptomatic but who is at low risk for bleeding, there may still be a role for the procedure," said Evans, who wasn't involved in the study.

The phase 3, multicenter trial randomized 692 patients with acute proximal DVT to receive either anticoagulation alone with warfarin (n=355) or anticoagulation plus pharmacomechanical thrombolysis (n=337).

The primary outcome was development of postthrombotic syndrome, which was defined as a Villalta score of 5 or higher or an ulcer in the leg with the index deep-vein thrombosis at 6 to 24 months.

Over the 24-month period, 47% of the 336 patients assigned to pharmacomechanical-thrombolysis and 48% of the 355 patients in the control group developed PTS, for a risk ratio (RR) of 0.96 (95% CI 0.82–1.11; P=0.56).

Major bleeding within 10 days occurred in 1.7% of the pharmacomechanical-thrombolysis group vs 0.3% in the control group (P=0.049).

The rate of recurrent venous thromboembolism within 24 months was 12% in pharmacomechanical-thrombolysis group. This included one fatal pulmonary embolism at 6 months. Among patients assigned to the control group, 8% had a recurrent venous thromboembolism (P=0.09).

Overall, there were 15 deaths, including seven in the pharmacomechanical-thrombolysis group and eight in the control group; but there were no deaths within 10 days of randomization.

Among secondary outcomes, pharmacomechanical thrombolysis was associated with a greater reduction in symptom severity compared with anticoagulation alone.

Moderate to severe postthrombotic syndrome, as defined by a Villalta score of 10 or greater, occurred in 18% of patients in the pharmacomechanical thrombolysis group, compared with 24% of those in the control group, for an RR of 0.73 (95% CI 0.54–0.98; P=0.04).

PTS severity was significantly lower in the pharmacomechanical-thrombolysis group than among controls at all follow-up visits from 6 to 24 months.

The pharmacomechanical-thrombolysis group also had greater decreases in leg pain than controls at 10 days (1.62 vs 1.29 Likert points) and at 30 days (2.17 vs 1.83 Likert points; P=0.03).

Leg circumference decreased by 0.26 cm from baseline at 10 days in the pharmacomechanical-thrombolysis group and increased by 0.27 cm from baseline in the control group (P=0.02).

At 30 days, leg circumference decreased by 0.74 cm in the pharmacomechanical-thrombolysis group, compared with 0.28 cm in the control group (P=0.05).

"The fact that the severity of symptoms seemed to be reduced by having the clot removal treatment suggests to me that there is something else going on. I think that there are other mechanisms involved and there are probably genetic differences between patients in terms of how much damage they sustain from a blood clot," Vedantham said.

"We know that inflammation, a generic name for a process by which the body reacts against the clot, differs among patients and may also influence the long-term outcome, and there may be other factors that we just don't know about. Certainly, the findings suggest that we should be looking also at other mechanisms for how this condition develops," he said.

"Future studies should be directed at particular groups of patients who may experience benefit from this therapy. There are some suggestions from the data that it's the patients with the largest blood clot and the most symptoms when they present, such as worse pain and swelling. However, that needs to be studied more carefully, and we cannot conclude this for sure," Vedantham said.

"I think the main take-home is that most patients can avoid an unnecessary procedure that would confer some risk and significant cost."

Disappointing Results

"For those of us who treat deep vein thrombosis and postthrombotic syndrome, it's disappointing that there was no difference in treatments," said Evans. More research is needed to figure out why postthrombotic syndrome develops and how best to address the problem.

"It's a huge problem in medicine, and pretty underrecognized. It would be a great area of research for young people entering medicine. There are so many unanswered questions, especially in this era of direct oral anticoagulants. What is their role in preventing postthrombotic syndrome?"

That patients who had a higher Villalta score had lower PTS rates suggests that the procedure does have some effect, Evans said.

"True, it doesn't reduce all the cases of PTS, and that makes me wonder if they had used a higher cutoff for the Villalta score, would they have seen a positive result? In my view, the limitation of the Villalta score is that a patient can have a history of DVT and have many leg symptoms that might be coming from something else but still meet the definition of postthrombotic syndrome. For me, that is problematic. I think more research needs to be done before we can say definitively that catheter-directed lysis does not work," she said.

The study was funded by the National Heart, Lung, and Blood Institute. Vedantham reported no relevant financial relationships. Disclosures for the coauthors are listed on the journal website. Evans reported no relevant financial relationships.

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