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ATTRACT trial shouldn’t detract from pharmacomechanical thrombolysis



– A closer look at the landmark ATTRACT trial of pharmacomechanical catheter-directed thrombolysis for acute deep vein thrombosis (DVT) shows multiple benefits for the intervention versus standard anticoagulation alone in the subset of participants with iliofemoral DVT, Kush R. Desai, MD, said at a symposium on vascular surgery sponsored by Northwestern University.

ATTRACT, a National Institutes of Health–sponsored, phase 3, multicenter, open-label, assessor-blinded study, was the first-ever randomized trial of pharmacomechanical catheter-directed thrombolysis (PCDT) for acute DVT.

The results caused a major stir because, despite a sound therapeutic rationale for the procedure, the incidence of chronic postthrombotic syndrome (PTS) at 24 months of follow-up was 47% in the PCDT plus anticoagulation group and 48% in controls on anticoagulation alone (N Engl J Med. 2017 Dec 7;377[23]:2240-52). Since then, that overall negative trial has been one of the hottest topics in DVT.

“This is the first thing your educated patients who come to the emergency department with DVT will ask about. It’s the first thing they’ll see when they go online and type in ‘thrombolysis DVT,’ ” noted Dr. Desai, an interventional radiologist at Northwestern University, Chicago.

But the trial has several major flaws, he cautioned. And contrary to popular opinion, ATTRACT is not the death knell for PCDT. Far from it.

“I don’t think the story stops with ATTRACT. This isn’t the end for PCDT in patients with iliofemoral DVT,” he asserted.

That’s in part because 301 of the 692 participants in ATTRACT had DVT of the femoropopliteal segment. That’s a population in which Dr. Desai and other interventionalists wouldn’t have anticipated seeing a benefit for PCDT, because their risk of PTS is so low.

“We know through historical data that patients with iliofemoral DVT are much more likely to develop PTS and to have recurrent DVT, so this is probably one of the major shortcomings of the trial,” he explained. “It’s through no fault of the trial investigators, because the study was planned years ago when we just didn’t know as much about PTS as we do now.

“The way I look at it is, I don’t practice in the way that ATTRACT was designed,” Dr. Desai said. “I don’t typically lyse or get referrals for lysis or thrombectomy in patients who have isolated femoropopliteal DVT. It has to involve at least the common femoral vein and frequently goes up to the iliac vein.”

The ATTRACT investigators’ recent subanalysis of the 391 participants with iliofemoral DVT showed that, although there was no difference between the two study arms in the occurrence of PTS through the first 24 months of follow-up, PCDT led to a 35% reduction in the incidence of moderate or severe PTS – by a margin of 18% versus 28% in controls.

Patients in the PCDT arm also experienced significantly greater improvement in venous disease-specific quality of life through 24 months, and a greater reduction in leg pain and swelling at 10 and 30 days (Circulation. 2018 Dec 4. doi: 10.1161/CIRCULATIONAHA.118.037425).

And moderate to severe PTS is a key outcome, Dr. Desai continued. Multiple studies have shown that patients with PTS have a worse quality of life than those with chronic lung disease, arthritis, or diabetes. Moreover, the 5%-10% of patients with symptomatic DVT who develop the most-severe form of PTS – characterized by severe pain, chronic ulcerations, stasis dermatitis, venous claudication, and intractable edema – have a quality of life comparable with patients with cancer or heart failure.

The 1.5% incidence of major bleeding within 10 days in the PCDT group was 200% higher than in controls, but none of it was life threatening.

“This is reassuring: Nobody had intracranial hemorrhage; nobody had a GUSTO 5 bleed,” Dr. Desai said.

Another limitation of the ATTRACT trial is that all but one of the devices utilized for PCDT were used off label. They weren’t designed for venous application. Several on-label rheolytic, rotational thrombectomy, or clot aspiration devices have been approved since enrollment in ATTRACT was closed. Future randomized trials will utilize on-label devices in patients with acute iliofemoral DVT to clarify the role of PCDT.

It’s noteworthy that nearly half of ATTRACT participants developed PTS within 24 months of their DVT despite being on optimal anticoagulation. It’s a finding that underscores the need for improved therapies. That was the impetus for development of first-generation catheter-directed thrombolysis utilizing a percutaneously inserted catheter to infuse a fibrinolytic drug directly to the thrombus to dissolve it rapidly.

But that form of catheter-directed thrombolysis has major disadvantages, Dr. Desai explained: It’s a multiday procedure requiring ICU-level care and prolonged exposure to powerful lytic agents.

“This is where things have changed with PCDT,” he said. “We can now, with on-label devices, accelerate the thrombolysis time, reduce lytic exposure, and I think also reduce the bleeding risk, although that hasn’t been shown in a trial yet. PCDT also reduces the necessity for ICU-level care and prolonged hospitalization.”

Dr. Desai no longer performs multiday lytic procedures. “In fact, with the introduction of the newer on-label devices, I haven’t done a multiday unilateral limb lytic procedure in a couple years. I think we’ve gotten to the point where we don’t need to do that anymore.”

Indeed, PCDT makes recanalization possible as a single-day, single-session procedure.

Dr. Desai views the recent ATTRACT subanalysis as hypothesis generating.

“Should PCDT be the first-line treatment in all proximal DVT patients? No it should not – and that’s not what I would have advocated even before ATTRACT came out,” he explained. “It’s sort of a salvage procedure for patients with iliofemoral DVT and moderate to severe symptoms. And there are a significant number of such patients.”

Current understanding of the pathophysiology of PTS is that a nondissolved thrombus at the valve leaflets becomes inflammatory, with resultant valvular dysfunction leading to venous reflux and venous hypertension. PCDT is consistent with the open-vein hypothesis, which posits that, by eliminating thrombus much faster than achievable via anticoagulation, valve integrity is maintained and PTS is prevented.

Dr. Desai reported receiving consulting fees from AngioDynamics, Boston Scientific, Cook Medical, and Spectranetics.

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