Ultrasound Plus Fibrinolysis Reduce Right Heart Dysfunction in Pulmonary-Embolism Patients

January 21, 2011

January 21, 2011 (Miami Beach, Florida) — Low-dose ultrasound energy administered in addition to thrombolytic therapy significantly reduces pulmonary clot burden and improves right heart function in patients with intermediate- and high-risk pulmonary embolism, new research shows [1].

"Most of the patients that we treat have submassive pulmonary embolism, accounting for about 40% of all pulmonary-embolism patients, and they have a 90-day mortality of about 22%," lead investigator Dr Tod Engelhardt (East Jefferson General Hospital, New Orleans, LA) told heartwire . "These patients present as pretty stable--they're short of breath, of course, but their blood pressure is all right. The interesting thing is that these patients have right heart enlargement, and we know that patients die from having large right ventricles, so the goal is to get that down to normal size. We got to find a way to do that that's safe and effective, and that's the whole point of this therapy."

Presenting data on the investigational therapy this week here at the International Symposium on Endovascular Therapy (ISET) 2011, Engelhardt said ultrasound-accelerated thrombolysis (EKOS, Bothell, WA) is designed to use ultrasound energy to loosen and thin the fibrin strands of the pulmonary clot, exposing the plasminogen-receptor sites. This increases permeability and thrombolytic penetration when drug therapy is administered, which helps the drug work faster, clear the clot sooner, and use a lower dose of fibrinolytic therapy.  

Aggressively Treating Submassive Pulmonary Embolism

To heartwire , Engelhardt explained that the guidelines recommend aggressive treatment of massive pulmonary embolisms, which occur in 5% of all patients and are associated with a 58% mortality rate at 90 days. These patients often present in cardiogenic shock and have a high early mortality rate due to right ventricular failure. Treatment involves intravenous thrombolytics and surgical/endovascular embolectomy to remove the thrombus.

Patients with submassive pulmonary embolism, on the other hand, are treated less aggressively, with guidelines recommending only that physicians consider intravenous therapy. Engelhardt said that aggressively treating submassive pulmonary embolisms makes sense because systemic thrombolysis can reverse right ventricular dilatation, which in turn lowers the risk of recurrent pulmonary embolism and chronic pulmonary hypertension. An improvement in the right-ventricle/left-ventricle ratio is also associated with a lower risk of mortality.

"The sooner that right heart dysfunction is corrected, the better the patient is going to be," said Engelhardt. "We also know that systemic fibrinolysis works, it's a large dose of tPA immediately, but there is a significantly increased risk of bleeding with it."

From February 2009 to July 2010, Engelhardt treated 27 pulmonary-embolism patients--three patients with massive pulmonary embolism--with the ultrasound technology in addition to 20 mg of tPA administered over a 12-hour period. Over 80% of patients who presented with the pulmonary embolism had a concomitant deep vein thrombosis (DVT).

All patients survived to hospital discharge. In terms of changes to the right ventricle, treatment with the ultrasound resulted in a significant reduction in the right/left-ventricle ratio and significantly reduced the modified Miller score, used to assess clot burden based on computed-tomography (CT) images. Symptoms also resolved within two to three hours after treatment was initiated.

Changes in the Right Heart Size and Clot Burden (Miller Score)

Parameter

Pretreatment

Posttreatment

p

Right/left-ventricle ratio

1.33

1.00

<0.001

Modified Miller score

17.8

8.7

<0.001

"Clinically, patients within two hours are not short of breath anymore," said Engelhardt. "That's a feel-good factor that I don't know how to measure, but I know that all of these patients, except the three massive [pulmonary embolism] patients who were intubated, go from a very anxious, impending-doom feeling to 'Doctor, I haven't felt this good in a long time.' "

In addition to symptom improvement, Engelhardt said the ultrasound technology has cut hospital length of stays by 50%. In the past, pulmonary-embolism and DVT patients were in the intensive care unit (ICU) for three or four days and discharged by day seven or 10. Now the patient is in the ICU for just 12 hours, during the ultrasound and tPA intravenous drip, and discharged by day five. 

Side Effects and Follow-Up

In terms of side effects, Engelhardt said there were no cases of intracranial hemorrhage or systemic bleeding complications in patients treated with the 20-mg dose of tPA. When investigators first started using the ultrasound technology, however, it was unknown how large a tPA dose was needed, he explained, and in patients treated with more than 20 mg, four developed major bleeding complications (average tPA dose 45 mg). Major bleeding was defined as a transfusion requiring more than one unit of blood.

In CT follow-up, taken at three months after treatment with ultrasound-accelerated thrombolysis, most patients have no evidence of clot, which is expected because the body's own fibrinolytic system kicks in to further break down the thrombus. In follow-up in one patient, however, seen three weeks after treatment, the clot was also completely gone, which is too soon for endogenous fibrinolysis to work.

"We know the half-life of tPA is pretty short," Engelhardt told heartwire . "Within 45 minutes it should be gone. I think what we're doing is decreasing the thrombus burden to the point where the body's own fibrinolytic system has an easier time, with less clot to work with."

There is an ongoing clinical trial in Europe, where the device has CE Mark approval, comparing the effectiveness of ultrasound-accelerated thrombolysis with anticoagulation alone for reversing right ventricular dilatation within 24 hours in patients with intermediate-risk/submassive pulmonary embolism. A single-arm trial, likely involving 100 patients from five or six clinical sites, is also under way in the US, and these data will be submitted to the Food and Drug Administration as part of device approval, said Engelhardt.

Engelhardt reports no conflicts of interest.

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