Editor's Note: Commentary based on 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.

Background

An acute pulmonary embolism (PE) is termed submassive in a normotensive patient with evidence of right ventricular dysfunction. This condition is common, occurring in 20-25% of patients with PE, and associated with a substantially increased risk of adverse outcomes.¹ Hemodynamic assessments, right ventricular dilation or hypokinesis, increased brain naturietic peptide levels, myocardial necrosis as evidenced by troponin release, and new electrocardiogram changes have each been associated with increased risk of poor outcome in an additive fashion. For example, a single center registry analysis noted a mortality rate of 6.6% in patients with right ventricular/left ventricular (RV/LV) ratio as assessed by echocardiography of ≥0.9 as compared to 1.9% in those below this cutoff.² Thrombolysis accelerates clot resolution but is infrequently used in current clinical practice. Current guidelines from the American Heart Association suggest consideration of fibrinolysis in patients with submassive PE with adverse prognosis, but randomized trial data to guide practice have been limited.³ The recently published PEITHO randomized trial in submassive PE patients with both RV dysfunction and elevated troponin randomized participants to systemic tenecteplase (weight-based dosing ranging from 30 to 50 mg) or placebo on a background of unfractionated heparin (UFH).⁴ Participants who received up-front lytic therapy were at decreased risk of hemodynamic compensation at the expense of an increase in both extra- and intracranial bleeding.

Methods

The Ultrasound Accelerated Thrombolysis of Pulmonary Embolism (ULTIMA) trial was a randomized, open-label, multicenter trial involving participants with acute PE involving at least one main or proximal lower lobe pulmonary artery and evidence of RV dilation as evidenced by RV/LV ratio ≥1.0 on an echocardiogram.⁵ Patients were excluded if they had known bleeding diathesis, hemodynamic compromise, recent surgery, or presentation late after symptom onset. Patients were randomized to treatment with either UFH alone or an ultrasound-assisted catheter-directed thombolysis (USAT) approach using an EkoSonic device (EKOS Corporation, Bothell, WA). The device incorporates ultrasound-mediated disruption of fibrin clot and increases thrombolytic clot penetration. Participants in the intervention arm received 10 mg of catheter-directed tenecteplase over 15 hours in either one or both affected lungs. The primary endpoint was the change in RV/LV ratio from baseline to 24 hours.

Results

Approximately 84% of patients screened failed to enter the study, most commonly because no proximal clot was present or the RV/LV ratio was <1.0. 59 patients ultimately underwent randomization, of which 90-day follow-up data were available in 57 patients. Mean age was 63 with average baseline heart rate of 88 beats per minute and blood pressure of 134/79 mm/Hg. The study met its primary endpoint; mean RV/LV ratio decreased from 1.28 to 0.99 over 24 hours with USAT as compared with 1.20 to 1.17 in those receiving UFH alone. Hemodynamic assessment <24 hours after USAT initiation noted a reduction in mean pulmonary artery systolic pressure from 52 to 40 mm Hg and an increase in cardiac index from 2.5 to 3.9 L/min/m². Death occurred in only one participant (UFH group), related to pancreatic cancer. No major bleeding was noted, although USAT was linked to two episodes of transient hemoptysis and one access-site groin hematoma. Hospital length of stay was similar between groups. Follow-up assessment at 90 days revealed no differences in mean RV/LV ratio (0.92 with USAT, 0.96 with UFH) or estimated pulmonary artery systolic pressure.

Conclusion

USAT is associated with accelerated improvement in hemodynamic and echocardiographic risk indices in patients with submassive PE with a reasonable safety profile.

Commentary/Perspective

The ULTIMA study provides the first randomized data involving a standardized catheter-based approach in the treatment of submassive PE. The rapid improvement in hemodynamics with USAT is similar in magnitude to that noted in trials with systemic thrombolysis with a substantially lower dose of lytic agent. Participants were relatively young with low risk of bleeding, limiting the generalizability of the results to the broader population. Study results were disappointing in that 90-day echocardiographic assessments were largely similar between the two groups. The study does not inform whether USAT might improve alternate clinical outcomes, such as mortality, hemodynamic collapse, functional status in follow-up, quality of life, or incidence of chronic thromboembolic pulmonary hypertension. Furthermore, optimal patient selection, timing/urgency of USAT, and the specific contribution of the ultrasound component of the intervention await further study. At present, the role of both systemic and catheter-directed thrombolysis in submassive PE remains uncertain. As recent and ongoing studies inform a more nuanced understanding, we may see a proliferation of multidisciplinary pulmonary embolism response teams that seek to provide expedited triage and management recommendations.⁶

References

1. Piazza G. Submassive pulmonary embolism. JAMA 2013;309:171-80.
2. Frémont B, Pacouret G, Jacobi D, Puglisi R, Charbonnier B, de Labriolle A. Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in patients with acute pulmonary embolism: results from a monocenter registry of 1,416 patients. Chest 2008;133:358-62.
3. 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.
4. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.
5. 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.
6. Provias T, Dudzinski DM, Jaff MR, et al. The Massachusetts General Hospital Pulmonary Embolism Response Team (MGH PERT): Creation of a Multidisciplinary Program to Improve Care of Patients With Massive and Submassive Pulmonary Embolism. Hosp Pract 2014;42:31-7.

Keywords: Disease Susceptibility, Echocardiography, Fibrin, Fibrinolytic Agents, Hemodynamics, Pulmonary Artery, Pulmonary Embolism, Tissue Plasminogen Activator

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