The objective of pharmacomechanical thrombolysis, or the delivery of a fibrinolytic drug into the thrombus with concomitant thrombus aspiration, is to diminish the thrombus burden and reduce the risk of post-thrombotic syndrome (PTS) in patients with proximal deep vein thrombosis (DVT). According to results from a randomized, controlled, phase III trial, though, the additional treatment failed to lower this risk, and increased the odds of experiencing major bleeding, compared with anticoagulation alone.
“Despite the use of anticoagulant therapy, PTS [which is associated with chronic limb pain and major disability] develops within two years in approximately half of patients with proximal DVT,” explained Suresh Vedantham, MD, of Washington University in St. Louis, Missouri, and co-authors. “We hypothesized that pharmacomechanical thrombolysis would reduce this percentage to 20 percent or lower,” but nearly half of patients enrolled in the multicenter, open-label trial still developed PTS within 24 months of DVT.
The ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) trial included 692 patients with symptomatic proximal DVT involving the femoral, common femoral, or iliac vein. Patients were excluded if they were symptomatic for >14 days, were at high risk for bleeding, had active cancer, had PTS, or had ipsilateral DVT in the previous two years.
Between December 2009 and December 2014, patients were stratified based on thrombus extent (i.e., whether thrombosis involved the common femoral or iliac vein or not), then randomized 1:1 to receive pharmacomechanical thrombolysis (n=336; median age = 52 years; range = 41-62 years) or no procedural intervention (control; n=355; median age = 53 years; range = 43-62 years).
Participants in both cohorts received initial and long-term anticoagulation consistent with published guidelines (including rivaroxaban when it became available) and received sized-to-fit, knee-high, elastic compression stockings at the 10-day follow-up visit and every six months.
In the pharmacomechanical thrombolysis group, recombinant tissue plasminogen activator <35 mg was administered into the thrombus.
Researchers assessed outcomes at 10 and 30 days, as well as six, 12, 18, and 24 months. They defined the development of PTS (primary endpoint) as a Villalta score ≥5 (score ranges from 0-33, with higher scores indicating more severe PTS) or an ulcer in the leg.
One patient in the pharmacomechanical thrombolysis group was excluded from analysis; five in the control group and 11 in the treatment cohort were excluded within seven days of randomization and were not included in per-protocol analysis.
The treatment cohort received pharmacomechanical thrombolysis a median of one day after randomization (range not provided), and the mean degree of thrombus removal was 76 percent (mean pre-procedure Marder score = 11.4; mean post-procedural Marder score = 2.7; change = –8.7%; 95% CI –8.1 to –9.4; p<0.001).
Over the 24-month period, 47 percent of patients in the treatment cohort (n=157/336) and 48 percent in the control group (n=171/355) developed PTS (risk ratio = 0.96; 95% CI 0.82-1.11; p=0.56). Incidence of PTS was similar among prespecified subgroups, except for a suggestion that patients 65 years and older were less likely to benefit from pharmacomechanical thrombolysis than younger patients (p=0.04).
Although patients in the pharmacomechanical thrombolysis group experienced less-severe PTS and lower venous clinical severity scores than the control group, there were also no between-group differences in change in venous disease-specific quality of life (p=-0.08) or general quality of life (p=0.37).
Six patients (1.7%) in the pharmacomechanical thrombolysis group experienced major bleeding within 10 days of treatment, compared with one patient (0.3%) in the control group (p=0.049). Recurrent venous thromboembolism within 24 months was reported by 42 patients (12%) in the treatment cohort (including 1 fatal pulmonary embolism at 6 months) and 30 patients (8%) in the control cohort (p=0.09).
Fifteen deaths occurred: seven in the pharmacomechanical thrombolysis cohort and eight in the control group, with all occurring at least 10 days after randomization, the researchers observed. “In the pharmacomechanical thrombolysis group, there were [earlier] major bleeds than in the control group, but less major bleeding (with no fatal or intracranial bleeds) occurred in association with the procedure than in past studies of thrombolysis for DVT,” they noted.
There was a “substantial number of missing assessments of PTS,” as well as missed follow-up visits, which the authors noted as limitations of the study. In addition, although many elements of the pharmacomechanical thrombolysis procedure were standardized, variations in how the procedure was performed to accommodate patient-specific differences and physician preferences further limited these findings.
Boston Scientific, Covidien (now Medtronic), and Genentech provided funding for the study.
The corresponding authors report financial support from Cook Medical, Volcano, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Portola, Bayer, and BTG/EKOS.
Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med. 2017;377:2240-52.