SEATTLE II: A New Way of Treating Pulmonary Embolism
Samuel Z. Goldhaber, MD: Hello. This is Dr. Sam Goldhaber for the Clot Blog at theheart.org on Medscape, speaking to you from the American College of Cardiology Scientific Symposium in Washington, DC. It is my great pleasure to introduce you to my very dear friend and colleague Dr. Greg Piazza, who is going to speak to us about a late-breaking clinical trial on submassive pulmonary embolism. Greg, welcome to the Clot Blog.
Gregory Piazza, MD: Thank you, Sam. It's a pleasure to be here.
Dr. Goldhaber: You and I have been working on therapies to improve the safety and the efficacy of advanced treatment of massive and submassive pulmonary embolism for quite some time. Could you tell us about your late-breaking clinical trial? [Editor’s note: Dr. Goldhaber is the study chair of the SEATTLE II trial.]
Dr. Piazza: I will be presenting a trial called SEATTLE II,[1] which is a study looking at ultrasound-facilitated, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. The foundation for the study comes from the understanding that systemic fibrinolysis at a full dose is associated with a high risk for bleeding, in particular intracranial hemorrhage. Utilization of fibrinolysis is pretty low in the United States because of concerns about intracranial hemorrhage, so there has been great interest in alternative therapies that might be safer. That was the impetus for the SEATTLE II trial.
We concentrated on patients who had proximal pulmonary embolism, with submassive or massive pulmonary embolism. Of interest, they had to have signs of right ventricular enlargement on chest CT, which we defined as a right ventricular (RV) to left ventricular (LV) ratio of at least 0.9.
These patients underwent ultrasound-facilitated fibrinolysis for either unilateral or bilateral pulmonary embolism. At 48 hours, we measured the change in RV:LV diameter ratio with CT scan -- and we measured pulmonary artery systolic pressures using echocardiography,. We also measured the pressures invasively.
Dr. Goldhaber: What was the hypothesis of the study?
Dr. Piazza: The hypothesis is that we would be able to effectively improve RV:LV diameter ratio and pulmonary artery systolic pressures safely.
Dr. Goldhaber: Would it shrink the size of the right ventricle?
Dr. Piazza: It would shrink the size of the right ventricle, and the size of pulmonary artery obstruction of the pulmonary embolism, but we had to do it with a low risk for intracranial hemorrhage.
Dr. Goldhaber: What was the safety hypothesis compared with standard systemic fibrinolysis?
Dr. Piazza: Our hope is that we would minimize the risk for intracranial hemorrhage and possibly have no intracranial hemorrhages in the trial.
Ultrasound-Facilitated Fibrinolysis
Dr. Goldhaber: You mentioned ultrasound-facilitated fibrinolysis. Can you explain to our Clot Blog/Medscape audience what that is all about?
Dr. Piazza: Sure. The device uses 2 catheters. An inner catheter is inserted into an outer catheter. The outer catheter is a drug infusion catheter that has side holes to elute the fibrinolytic drug -- in this case, the tissue plasminogen activator (tPA) alteplase.
Inside that catheter is a smaller catheter called the "ultrasound core catheter." This catheter has ultrasound transducers at regularly spaced intervals that produce a low level of ultrasound, such as might be used to diagnose a deep vein thrombosis.
This creates 2 things. One is a process called "acoustic streaming," in which mechanical forces push the tPA closer to the thrombus. The second process is called "conditioning," in which the fibrin strands (which are normally in a very tight lattice) spread apart to allow greater porosity of the fibrin network and greater penetration of the tPA into the thrombus.
Dr. Goldhaber: How many patients were enrolled in this late-breaking clinical trial?
Dr. Piazza: We enrolled 150 patients.
Dr. Goldhaber: How many had massive and how many had submassive pulmonary embolisms?
Dr. Piazza: We were very pleased to see that 21% of patients had massive pulmonary embolism.
Dr. Goldhaber: That is quite a few.
Dr. Piazza: Yes.
Dr. Goldhaber: Can you encapsulate the results of this trial?
Dr. Piazza: We uncovered that the procedure itself was able to be completed successfully 98% of the time. We treated 86% of patients with bilateral disease, and we were able to show that the RV:LV ratio decreased by 30% from the start of the procedure to when the 48-hour CT scan was performed. On top of that, we were able to show that the pulmonary artery systolic pressures also decreased by 30% from the start of the procedure to the completion of the procedure.
We looked at how submassive and massive pulmonary embolism patients performed in the study, and there was no difference in the response. Both groups had a very good response. The pulmonary artery angiographic obstruction score (the modified Miller index) also decreased by 30% from before the procedure to after.
Safety of the New Interventional Approach
Dr. Goldhaber: Is this done in a catheterization lab or an interventional radiology lab? Tell us about safety.
Dr. Piazza: Safety was a key focus of the study. We were able to show that the rate of intracranial hemorrhage from this procedure was zero.
Dr. Goldhaber: Our historical findings with systemic fibrinolysis and full-dose tPA (100 mg over 2 hours) showed a 2.5%-3% rate of intracranial hemorrhage.[2] And in your study it was zero?
Dr. Piazza: Here it was zero.
Dr. Goldhaber: The typical US Food and Drug Administration (FDA)-approved dose for systemic fibrinolysis is 100 mg. What was the dose of tPA in this study?
Dr. Piazza: The design of the study regulated the dose at 24 mg.
Dr. Goldhaber: Essentially one fourth of the systemic dose?
Dr. Piazza: Exactly, and in the study that is exactly what the mean dose was: 24 mg.
Dr. Goldhaber: Do you think it is the lower dose that explains the absence of intracranial hemorrhage in this trial?
Dr. Piazza: That might be part of it -- the fact that it is one quarter of the usual dose. Also, introducing the fibrinolytic drug very close to the thrombus helps to keep it localized in the area where it is needed as opposed to having a large systemic effect.
Dr. Goldhaber: These sound like very promising results. Now, on the basis of this trial, how would you decide when to administer full systemic, peripheral intravenous thrombolysis vs using the ultrasound-facilitated approach?
Dr. Piazza: For patients with a very low risk for bleeding, who present with massive pulmonary embolism and need rapid care but in whom it may take a longer to mobilize the cardiac catheterization lab, systemic fibrinolysis still has a very important role. But when we have time to offer the patient a safer procedure for rapid dissolution of a pulmonary embolism, I would consider catheter-based fibrinolysis with ultrasound.
Dr. Goldhaber: This might have tremendous implications. If we apply it to massive and submassive pulmonary embolism, we are talking about 25%-30% of the entire gamut of patients with pulmonary embolism, right?
Dr. Piazza: That's correct. We may be seeing is a transition from how we treat pulmonary embolism that is very similar to what we saw with myocardial infarction. You will remember at first using systemic fibrinolysis for myocardial infarction and then with greater experience in the cath lab, we moved to an interventional approach. We may see that very same phenomenon occurring right now with pulmonary embolism.
Dr. Goldhaber: We are on the cusp of a potentially new era in advanced therapy of pulmonary embolism. Greg, thank you very much for joining us at the Clot Blog on Medscape.
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Cite this: SEATTLE-II: A New Era for Massive and Submassive PE - Medscape - Apr 17, 2014.
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