Editor’s Note: Commentary based on Kucher N, Boekstegers P, Müller O, et al. Randomized controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129:479-86.

Background

Acute pulmonary embolism (PE) continues to be difficult to manage despite increasingly sophisticated diagnostic and therapeutic tools. Mortality and morbidity remain high in patients with hemodynamic compromise (massive or high-risk PE) or evidence of right ventricular dysfunction (submassive or intermediate-risk PE).¹ Systemic thrombolytic therapy reduces mortality in patients with massive PE, but its utilization is hampered by real and perceived risks of serious bleeding, including intracranial hemorrhage.² The use of systemic thrombolytic therapy in patients with submassive PE remains controversial after completion of several randomized trials.^3-5 As such, catheter-directed thrombolysis represents an attractive option to target the treatment to the pulmonary arteries while avoiding the dreaded complications of ST.  The Ultrasound Accelerated Thrombolysis of PE (ULTIMA) trial⁶ studied the effect of ultrasound-assisted catheter-directed thrombolysis in reversing right ventricular dysfunction in patients with submassive PE.

Methods

From 2010 to 2013, Kucher et al. enrolled 59 patients (363 screened) with intermediate-risk PE (defined as clinically stable but with right ventricular [RV]/left ventricular [LV] ratio ≥1 by echocardiography) at eight hospitals in Germany and Switzerland. In open-label fashion, patients were randomized to receiving ultrasound-assisted catheter-directed thrombolysis plus intravenous unfractionated heparin (UFH) group versus receiving UFH alone. The ultrasound-assisted catheter-directed thrombolysis group received fixed-dose infusion of recombinant tissue plasminogen activator (rtPA) using the EkoSonic catheter at 10 mg per treated lung over 15 hours (20 mg administered for bilateral PE, delivered by two catheters). The primary endpoint was the echocardiographic difference in RV/LV ratio at 24 hours, analyzed by a core laboratory blinded to treatment assignment. Safety outcomes included death, hemodynamic decompensation, major and minor bleeding, as well as other serious adverse events up to 90 days after randomization.

Results

Procedural success was achieved in 100% of the ultrasound-assisted catheter-directed thrombolysis group. The mean RV/LV ratio in the ultrasound-assisted catheter-directed thrombolysis group decreased from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (P <0.001), compared to a non-significant change from 1.20±0.14 at baseline to 1.17±0.20 in the heparin-only group. In addition, there was significantly more recovery of RV systolic function in the ultrasound-assisted catheter-directed group at 24 hours (55% with mild or no dysfunction) as well as at 90-day follow-up (100%) compared to the heparin-only group (36%, P = 0.01 and 93%, P = 0.003, respectively).  At 90 days, there were no deaths or hemodynamic decompensation in the ultrasound-assisted catheter-directed thrombolysis group, and one death due to cancer in the heparin-only group.  There were no major bleeding complications in either group. Three minor bleeding events (including one access site hematoma) occurred in the ultrasound-assisted catheter-directed thrombolysis group and one in the heparin-only group (P = 0.61).

Conclusion

Ultrasound-assisted catheter-directed thrombolysis using fixed-dose rtPA is superior to heparin alone in improving RV function in patients with submassive PE. Ultrasound-assisted catheter-directed thrombolysis appears safe from bleeding complications, although this trial was not powered to study this endpoint.

Perspective/Commentary

The key benefit of catheter-directed thrombolysis for acute PE is a profound reduction in the amount of thrombolytics used—doses used in ULTIMA were 10 and 20% of typical systemic thrombolytic doses (unilateral vs. bilateral PE, respectively). This serves to minimize the often dramatic consequences of hemorrhage due to systemic exposure to thrombolytics. ultrasound-assisted catheter-directed is one of several available catheter-directed thrombolysis products, using ultrasound energy to separate aggregated but un-cross-linked fibrin molecules and, thus, enhancing permeation of thrombolytics into thrombus.⁷ The EkoSonic system combines ultrasound with drug infusion in a small profile catheter (6F), which are beneficial to patients and interventional physicians.

Despite the significant buzz generated by ULTIMA (e.g., evidence of significant hemodynamic benefit and absence of serious bleeding events), it remains a small Phase-II trial using echocardiography-driven surrogate endpoints. No conclusions could be drawn regarding efficacy and safety of ultrasound-assisted catheter-directed. A larger, single-arm trial (A Prospective, Single-arm, Multi-center Trial of EkoSonic Endovascular System and Activase for Treatment of Acute Pulmonary Embolism [SEATTLE II]) has been conducted to address these clinical endpoints. If additional trials aim to establish noninferiority in efficacy against systemic thrombolysis and safety against UFH alone, it is conceivable, even likely, that catheter-directed thrombolysis might replace systemic thrombolysis as the preferred treatment option in patients with massive or submassive PE.

References:

1. Piazza G. Submassive pulmonary embolism. JAMA 2013;309:171-80.
2. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011:123:1788-830.
3. Sharifi M, Bay C, Scrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol 2013:111:273-7.
4. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost 2014;12:459-68.
5. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.
6. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129:479-86.
7. Braaten JV, Goss RA, Francis CW, et al. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemos 1997;78:1063-8

Keywords: Biomarkers, Echocardiography, Fibrin, Fibrinolytic Agents, Follow-Up Studies, Germany, Hematoma, Hemodynamics, Heparin, Intracranial Hemorrhages, Neoplasms, Prospective Studies, Pulmonary Artery, Pulmonary Embolism, Random Allocation, Switzerland, Thrombolytic Therapy, Thrombosis, Tissue Plasminogen Activator, Ventricular Dysfunction, Right

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