Ultrasound-Assisted Thrombolysis Fails to Boost Thrombus Resolution in Acute Iliofemoral DVT
Adding intravascular ultrasound energy does not improve the efficacy of catheter-directed thrombolysis therapy in patients with acute iliofemoral deep vein thrombosis (DVT), according to a randomized trial published in the January 2015 issue of Circulation: Cardiovascular Interventions. Despite these findings, the procedure was demonstrated to be safe.
“Given the higher costs of the [ultrasound-assisted catheter-directed thrombolysis] catheter system compared with conventional …] multisidehole catheters, our data question the usefulness and particularly the cost-effectiveness of adding intravascular ultrasound for the treatment of acute iliofemoral DVT,” Nils Kucher, MD, of University Hospital Bern (Bern, Switzerland), and colleagues conclude.
The single-center BERNUTIFUL trial included 48 patients (mean age 50 years; 52% female) with acute iliofemoral DVT and symptom duration of less than 2 weeks. All patients were treated with EkoSonic MACH 4 Endovascular System catheters (EKOS Corporation), which consist of a control unit, a drug-delivery catheter, and ultrasound transducers (which were switched on only in the ultrasound-assisted group). The thrombolysis regimen was 20 mg of recombinant tissue plasminogen activator (tPA) delivered in a continuous infusion over 15 hours.
At initial presentation, patients received an IV bolus of unfractionated heparin 80 U/kg of body weight unless they had already been treated with unfractionated heparin, low molecular weight heparin, fondaparinux, or oral anticoagulation before study enrollment. During catheter thrombolysis, unfractionated heparin was infused through the venous access sheath, with adjustments made every 6 hours to ensure an activated partial thromboplastin time corresponding to therapeutic heparin levels.
There were no differences between the ultrasound-assisted and conventional groups in terms of the average treatment zone length of the catheter system (41 vs 44 cm; P = .25) or the mean tPA dose per treatment zone cm (0.56 vs 0.47 mg/cm; P = .26).
After thrombolysis, patients in both groups had significant reductions from baseline in thrombus burden, but there was no difference between the groups. The percentage of thrombus load reduction from baseline to 15 hours according to length-adjusted thrombus score derived from standardized venograms (primary endpoint) was 55% with ultrasound assistance and 54% with the conventional approach (P = .91).
Symptom duration and tPA dose per treatment zone were not associated with the degree of thrombus load reduction.
Though the percentage of patients who underwent adjunctive catheter-based thrombus removal therapy was numerically lower in the ultrasound-assisted group than in the conventional group, the difference did not reach statistical significance (29% vs 46%; P = .37). Additionally, other outcomes, including the need for adjunctive angioplasty and stenting, treatment-related complications, bleeding, and hospital length of stay, were similar regardless of treatment group.
At 3-month follow-up, primary venous patency was demonstrated in 100% and 96% of patients in the ultrasound-assisted and conventional groups, respectively (P = .33). The severity of postthrombotic syndrome and disease-specific quality of life were comparable as well.
Reasons for Lack of Efficacy Unclear
Current guidelines recommend percutaneous catheter-based techniques as first-line therapy for selected patients with iliofemoral DVT, and catheter-direct thrombolysis has been shown to reduce postthrombotic syndrome.
Some evidence exists to support the idea that intravascular ultrasound improves the efficacy of the approach. “According to in vitro studies, ultrasound causes reversible disaggregation of uncrosslinked fibrin fibers, and ultrasound pressure waves increase thrombus penetration of thrombolytic drugs by acoustic streaming,” Dr. Kucher and colleagues write, noting that the utility of ultrasound assistance remains controversial.
Based on the current findings, they conclude “that the in vitro effects of high-frequency (2.2 MHz), low-power (0.5 W) ultrasound—that is, fibrin separation and acoustic streaming—cannot be translated to patients with acute iliofemoral DVT,” adding that the reason for this is uncertain.
“Thrombus age is highly variable in patients with acute DVT and might not be comparable to thrombosis generated [in] in vitro or in vivo experiments. Although the ultrasound frequency of 2.2 MHz is certainly appropriate to penetrate thrombus, the low power of 0.5 Watt per ultrasound element might be insufficient to obtain a substantial effect on thrombus resolution,” they explain.
“Further studies are required to show whether an increase in ultrasound energy may enhance thrombolysis without causing harmful effects, including damage to veins and surrounding tissue from cavitation,” they continue. “It also remains unclear whether an increase in ultrasound energy is feasible at all because end of life of individual ultrasound elements frequently occurs beyond 24 hours with delivery of low-power energy.”
The authors point out that the findings cannot be extrapolated to other vascular beds, including the pulmonary or peripheral arteries.
Engelberger RP, Spirk D, Willenberg T, et al. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis. Circ Cardiovasc Interv. 2015;Epub ahead of print.
- The study was supported by the Swiss National Science Foundation and the Swiss Heart Foundation.
- Dr. Kucher reports serving as a consultant for Bayer and EKOS Corporation and receiving honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis.