New Devices

Ultrasound-Assisted, Catheter-Directed, Low-Dose Thrombolysis: A Safer Alternative to Systemic Thrombolytics for Pulmonary Embolism

Anas Safadi, MD, St. Mary Medical Center, Hobart, Indiana

Anas Safadi, MD, St. Mary Medical Center, Hobart, Indiana

Disclosure: Dr. Safadi reports no conflicts of interest regarding the content herein. 

Dr. Anas Safadi can be contacted at


Pulmonary embolism (PE) is common, occurring in more than 600,000 people in the United States annually.1 One 25-year population-based study found the annual incidence of PE to be 69 per 100,000 people.2 PE has high mortality rates, causing an estimated 200,000 deaths per year in the U.S., and it is the third most common cause of death in hospitalized patients.3 

Massive PE patients present with systemic arterial hypotension, cardiogenic shock, or cardiac arrest.4 These patients, accounting for approximately 5% of the PE population, are associated with a mortality rate of 58% at 3 months. Submassive PE, which affects 40% of patients with PE, characterizes patients with right ventricular (RV) dysfunction while maintaining systemic normotension, and reports a 21% mortality rate at 3 months.5 The presence of RV dysfunction has demonstrated to be a marker for poor outcomes, including increased risks of mortality and clinical sequelae. 

Immediate and aggressive thrombolytic therapy is warranted in patients with massive PE. Patients with submassive PE may also be candidates in some cases for systemic thrombolysis, if they have an adverse prognosis due to large thrombus burden, severe RV dysfunction, major myocardial necrosis, or significant respiratory insufficiency.4 With the exception of submassive PE, while thrombolytic therapy is associated with lower all-cause mortality than anticoagulants, it carries an elevated risk of intracranial and major bleeding. A meta-analysis found a 9.24% rate of major bleeding with thrombolytic therapy versus 3.42% with anticoagulation therapy.6 The recent PEITHO trial, which randomized patients with intermediate-risk PE to tenecteplase plus heparin or to placebo plus heparin, found that hemorrhagic stroke occurred in 2.0% of patients receiving fibrinolytic therapy versus 0.2% in the placebo group. Major bleeding occurred in 11.5% in the treatment group, compared to 2.4% in the heparin-alone group.7

Ultrasound-assisted, catheter-directed, low-dose thrombolysis, facilitated by the EkoSonic Endovascular System (EKOS Corporation) has emerged as a much safer, faster, and more efficacious treatment for acute massive and submassive PE than systemic thrombolytics. Data from two multicenter trials clearly show that the technology improves RV function and other hemodynamic parameters, such as cardiac output and pulmonary artery pressure, within 24 hours of treatment, with very low risk of intracranial and major bleeding. 

The ULTIMA study, a randomized, controlled trial, randomized 59 patients with intermediate-risk (or submassive) PE to unfractionated heparin and low-dose ultrasound-assisted, catheter-directed thrombolysis or to unfractionated heparin alone. The mean decrease in RV/left ventricular (LV) ratio from baseline to 24 hours was a substantial 0.30 ± 0.20 in the ultrasound-accelerated thrombolysis group versus an insignificant reduction of 0.03 ± 0.16 in the anticoagulation with the heparin-alone group. There was no evidence of major bleeding in the ultrasound-accelerated thrombolysis group; some patients had minor bleeding that didn’t require medical intervention. The patients who had the ultrasound-accelerated thrombolysis procedure had also quickly improved their pulmonary thrombus burden; as measured by a modified Miller score, pulmonary thrombus burden was also substantially reduced.8

The SEATTLE II study, a prospective, multicenter trial, evaluated the safety and efficacy of ultrasound-facilitated, catheter-directed, low-dose thrombolysis with the EkoSonic Endovascular System in 150 patients with acute massive or submassive PE. The mean RV/LV ratio in the study decreased from 1.55 pre-procedure to 1.13 at 48 hours post-procedure, a statistically significant and substantial difference of 0.42. The technology rapidly relieved pulmonary artery obstruction and reduced pulmonary hypertension, with no reports of intracranial hemorrhage.9 

Unlike systemic thrombolysis, which delivers a 100 mg tPA dose to treat acute massive PE, ultrasound-assisted catheter-directed thrombolysis directs a much reduced lytic dose of 24 mg locally within the clot over 12 to 24 hours. By using only a fraction of the IV dose of tPA, the risk of significant bleeding with the ultrasound-assisted technology is greatly minimized.

There have been no studies to date that demonstrate that Ekos therapy reduces long-term mortality from PE. But it stands to reason that a procedure that quickly relieves strain on the heart will also reduce complications such as chronic pulmonary hypertension, thereby possibly improving long-term mortality. 

Case presentation

A 73-year-old white female developed uncontrolled hypertension while in the rehabilitation inpatient unit of our hospital. She had been receiving physical therapy after a below-the-knee amputation resulting from gangrene in her left foot. The patient also had a history of hyperlipidemia, hypertension, diabetes, and peripheral vascular disease. Her hypertension medication was titrated, but 12 days later, she suddenly became hypotensive and unresponsive, with a systolic blood pressure of 73 mm Hg. Absent any classic symptoms of PE, we believed at the time that she had received too much pain medication. 

She was transferred to the ICU, pressors were started, and cardiac markers were ordered to look for signs of a myocardial infarction, along with a D-dimer test. The patient’s very high D-dimer value of 4.47 (normal range is ≤0.50 mcg/mL fibrinogen equivalent units) indicated that she probably had a significant thrombus. A computed tomography pulmonary angiogram showed a very large bilateral PE affecting the middle and upper lobes of the right pulmonary artery, and the upper and lower lobes of the left pulmonary artery. The patient also had evidence of right ventricular strain with a RV/LV diameter ratio of 1.9. Her pulmonary artery pressures were 39/13 with a mean of 22, consistent with mild pulmonary hypertension, and she required high-flow oxygen.

Two Ekos catheters were placed, one in the right and one in the left pulmonary arteries, which infused tPA at the rate of 1 mg/hour/catheter for a total tPA dose of 24 mg. The patient returned to the ICU. Twelve hours later, her blood pressure was stable at 114/53, she was weaned off pressor support, and she was receiving only nasal cannula oxygen supplementation. The catheters were removed in the ICU and she was prescribed anticoagulation medication. The patient stabilized from a hemodynamic standpoint after treatment and continues to do well long term. 


In the case described, the patient had a life-threatening PE. Ultrasound-assisted, catheter-directed, low-dose thrombolysis rapidly reduced her pulmonary artery pressure and RV strain, and facilitated her RV recovery, making a significant difference in her acute and long-term outcomes. Had she received standard of care and survived, she may have been at high risk for poor outcomes, such as chronic pulmonary hypertension. 

Over the last two years, we have performed at least 50 procedures using ultrasound-assisted, catheter-directed thrombolysis to treat PE (a second case example can be seen in Figures 1A-D). Unlike other emerging interventional procedures, this technology is easy to master and quick to perform; the procedure time for a bilateral PE is approximately 25 minutes. We would be hard pressed not to offer Ekos therapy to patients with massive PE, as well as select patients with submassive PE, given the technology’s minimal risk of major bleeding and low rate of adverse effects. Patients with non-massive PE, however, require standard anticoagulation and are not candidates for ultrasound-assisted, catheter-directed thrombolysis. This therapy is also not indicated for patients with a significant risk of bleeding. While additional trials are needed to evaluate mortality reduction and long-term outcomes of Ekos therapy, there is a growing body of evidence to support this treatment for a large percentage of patients with acute PE. 


  1. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002; 121: 877-905. 
  2. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998; 158: 585-593. 
  3. McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. 46th ed. New York: McGraw-Hill Companies Inc; 2007.
  4. 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(16): 1788-1830.
  5. Goldhaber S, Visani L, DeRosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999; 353(9162): 1386-1389. 
  6. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: A meta-analysis. JAMA. 2014; 311(23): 2414-2421. 
  7. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014; 370: 1402-1411.
  8. 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(4): 479-486.
  9. Piazza G. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism (SEATTLE II). American College of Cardiology 63rd Annual Scientific Session, Washington D.C., March 30, 2014.