Clinical Trial Update

SEATTLE II: Ultrasound-Facilitated, Catheter-Directed, Low-Dose Thrombolysis for Acute Pulmonary Embolism

Cath Lab Digest talks with Gregory Piazza, MD, MS, Brigham and Women’s Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts.

Cath Lab Digest talks with Gregory Piazza, MD, MS, Brigham and Women’s Hospital, Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts.

Disclosure: Dr. Piazza reports  research grant support from  BTG/EKOS Corporation. 

Dr. Gregory Piazza can be contacted at gpiazza@partners.org.

Can you give us a brief history and overview of SEATTLE II, and share the trial results?

Historically, for decades, we have only had one FDA-approved therapy for treatment of patients with high risk or intermediate risk pulmonary embolism, and that was systemic fibrinolysis. Although trials and meta-analyses have shown that systemic fibrinolysis does have a benefit by preventing cardiovascular collapse — it even appears to improve mortality — it is associated with a high risk of intracranial hemorrhage and major bleeding. For that reason, there has been great interest in alternative techniques that might use some amount of fibrinolytic drug, but much less than the systemic dose, and might give it locally in a way that would enhance the drug’s efficacy for breaking up the pulmonary embolism. There has been great interest in catheter-based techniques. One of the most advanced catheter-based techniques from a research-based standpoint is ultrasound-facilitated, catheter-based, low-dose fibrinolysis, or the EKOS procedure, which is what we studied in SEATTLE II. SEATTLE II was a prospective trial looking at patients with massive and submassive pulmonary embolism. Massive pulmonary embolism includes patients that have hemodynamic instability, shock, hypotension, cardiac arrest, syncopy, or respiratory failure. Submassive pulmonary embolism describes patients who have normal blood pressure, but signs of right ventricular dysfunction. Low-risk pulmonary embolism includes the remaining patients. SEATTLE II focused on massive and submassive pulmonary embolism patients, and they had to have some sign of right ventricular (RV) enlargement. We defined that as a RV to LV (left ventricular) ratio on a computed tomography (CT) scan of 0.9 or greater. These patients underwent an ultrasound-facilitated, catheter-based, low-dose fibrinolytic procedure where they received tPA through the catheter. If patients had unilateral disease, they had one catheter that infused 1 mg/hour of tPA for 24 hours. If patients had bilateral disease, they had catheters placed on both sides, and received 1 mg/hour through each catheter for just 12 hours. That way, every patient got the same amount of tPA, 24 mg. We assessed the CT-measured change in RV to LV ratio at 48 hours, as well as the measures for pulmonary angiographic obstruction and pulmonary hypertension. We observed a 25% reduction in the RV to LV diameter ratio. That ratio is actually a surrogate marker for pulmonary embolism mortality, so we were pleased to see that it had decreased so quickly, 48 hours after the start of the procedure. We observed a 30% reduction in pulmonary artery systolic pressure from the beginning of the procedure to the end of the procedure, and that held true out to 48 hours when we did an echocardiogram to assess pulmonary artery pressure. Pulmonary angiographic obstruction, defined using a modified Miller index, decreased by 30%. We observed a 10% major bleeding rate, but most of those bleeds were only GUSTO moderate bleeds. We had an all-inclusive definition for major bleeding that included GUSTO severe and life threatening as well as GUSTO moderate. All except one of those bleeds was a GUSTO moderate. We didn’t observe any intracranial hemorrhage.

Is bilateral pulmonary embolism considered more serious?

It is really the patient’s response to the pulmonary embolism that determines whether it is high risk or low risk. It is what happens to their right ventricle and what happens to their hemodynamics. Anatomic distribution is less important.

What has been the impact of SEATTLE II and how has it affected your thinking?

The issue with systemic fibrinolysis is the concern of major bleeding and intracranial hemorrhage. Now we have published these data on a catheter-based approach. These data resulted in FDA approval of the EKOS device for treatment of acute pulmonary embolism. In light of the FDA approval and the data we have provided, as well as the earlier trials, I think that there is enough evidence to include this technique as one of our tools for acute pulmonary embolism or those pulmonary embolism patients at an increased risk for adverse outcome.

What about patients who can’t be treated with the EKOS system?

Patients with absolute contraindications to fibrinolytic therapy can still be considered for open surgical pulmonary embolectomy or inferior vena cava (IVC) filter placement.

What are the dangers of prolonged right heart enlargement?

Patients with RV dysfunction have an increased risk of developing outright RV failure, cardiovascular collapse, shock, and even death. What has been observed with systemic fibrinolysis is a very prompt recovery of the right ventricle, similar to what we observed in SEATTLE II. We didn’t compare the techniques directly, so you can’t make too strong of a comparison, but both therapies have shown prompt improvements in RV function.

Did SEATTLE II look at long-term improvement? 

We followed patients for 30 days, what would be considered short-term follow-up. In the future, we will conduct investigations that focus on more long-term outcomes. Previous studies that have looked at systemic fibrinolysis have shown that the right ventricle appears to recover quickly and so most of the recovery of the right ventricle will occur within those first 30 days. Some patients will have some additional recovery. Things like pulmonary hypertension may improve on a longer follow-up basis, and that is something we will need to look at.

What about complications?

The greatest fear is intracranial hemorrhage, because many times those events are either disabling or fatal for patients. In the studies of systemic fibrinolysis, when you look at randomized, controlled trials or registries, it is somewhere in the range of 2-5%. In all of the studies with the ultrasound-facilitated, catheter-based fibrinolysis there were no episodes of intracranial hemorrhage. That is a substantial improvement in safety. When it comes to major bleeding, just major bleeding in general, which can include intracranial hemorrhage, but also includes gastrointestinal (GI) bleeding and retroperitoneal bleeding, registries with systemic fibrinolysis have shown a rate of about 20% major bleeding. In SEATTLE II, we observed a rate of around half that. It is hard to draw comparisons between registry data and a clinical trial, but it does appear that using a lower dose of fibrinolysis and giving it locally appears to be safer.

What about time and cost with the EKOS system?

Those are important factors for any angiography lab or hospital that is interested in incorporating this technology into their algorithms for treating patients with pulmonary embolism. There is an increased cost for doing this procedure, since it requires use of an angiography suite. It will require either a step-down unit stay or an intensive care unit (ICU) stay for infusion of the tPA. Ways to make the EKOS procedure more efficient are being actively investigated. The hope is now that the technology has been proved to be effective and safe, that additional modifications such as decreasing the infusion time and lowering the dose will further facilitate this type of procedure and make it less resource-intensive. 

What discipline has traditionally handled pulmonary embolism patients?

It really varied hospital to hospital. In some hospitals, it was the cardiovascular medicine providers; in other medical centers, it could have been pulmonologists, hematologists, cardiac surgeons, or interventional radiologists. Pulmonary embolism, for a long time, was kind of an “orphan” disease where there wasn’t one specialty that took ownership of it. As time has gone by, people have developed multidisciplinary pulmonary embolism response teams and it is now more of a collaborative approach between specialties. At Brigham and Women’s Hospital, we do have a multidisciplinary pulmonary embolism response team. These response teams will also help to spread awareness and propagate evidence-based approaches to pulmonary embolism. 

Who is on the team at Brigham and Women’s Hospital?

Our team includes pulmonary vascular disease specialists, radiologists, cardiac surgeons, interventionalists, and cardiologists. 

If a pulmonary embolism patient comes in, what happens?

An on-call pulmonary embolism response team physician evaluates the patient immediately, then confers with the attending that is on call. The case is presented, imaging is reviewed, and then a decision is made about additional specialists that need to be added to the phone call in order to consider advanced therapy. For example, if the patient needs to go for a surgical pulmonary embolectomy or needs to be evaluated for surgery, then cardiac surgery would be involved. 

How long has the team been up and running? 

Over a year. This type of approach has been popular over the last couple of years. We had something similar in place before it was developed as a more formal team, so we have actually been doing something like this for a while. The formally organized pulmonary embolism response team, where we are actually tracking the utilization of the team and outcomes, has occurred over the last year.

Is pulmonary embolism similar to a ST-elevation myocardial infarction, where there is a certain window of opportunity for best outcomes?

It’s probably not a fair analogy. Pulmonary embolism has a much higher 90-day mortality than myocardial infarction. If anything, these patients are more acute in some ways. They often have more co-morbidities. Massive pulmonary embolism patients need to be treated aggressively, on the order of minutes to hours, whereas patients with submassive or intermediate risk pulmonary embolism should receive advanced therapies, if appropriate, over the course of a 24- to 48-hour period.

What are common co-morbidities with these patients?

It is very common in the setting of heart failure, chronic obstructive pulmonary disease, chronic kidney disease, cancer, post-surgical states, and post-trauma states. Having one or more of those conditions actually increases the morbidity of the pulmonary embolism and it can complicate management. Myocardial infarction patients can have co-morbidities, but there is not an association like there is with pulmonary embolism, in particular with cancer or major surgery.

Can you describe the learning curve for the EKOS system?

I don’t do the procedure myself, but the placement of the catheters is very similar to placing a pulmonary artery catheter or performing a right heart catheterization, so I’m told it is not something that is terribly technically- or labor-intensive. Most centers are able to adopt the technology fairly quickly.

What are the plans for the future?

Once we have focused on making the procedure more efficient and have really honed down the dose and an infusion time that works well, but also maintains the efficiency of the procedure, then we will focus on long-term outcomes, which can include things like functional status, exercise capacity, and pulmonary hypertension.

Considering efficiency, since the bilateral patients had a reduced infusion time (12 hours), how did they do compared to the unilateral patients (24 hours)?

They had similar results. Even though bilateral patients had a decreased infusion time, it was the same dose of tPA, and we wouldn’t necessarily expect the infusion time to have much impact other than making things more efficient through a shortened infusion time. In the study we are conducting now, called OPTALYSE PE, we are testing a number of different permutations of infusion time and dose to see which provides efficacy with the optimal efficiency. Just shortening the infusion time wouldn’t be expected to change much, except the efficiency, whereas efficacy is probably more dependent on the dose. If you shorten the infusion time, like we are aiming to do in OPTALYSE PE, there is the potential that patients could get the catheters placed, go to the cath lab or angio suite holding area, get their infusion, and then go back to the cath lab for a re-look, without ever having to go to the ICU or a step-down. That would really decrease costs and improve efficiency.

One of your specialties is in treatment of deep vein thrombosis (DVT). Are there any possibilities for treatment with the EKOS system?

It is under active investigation and is definitely another area where this procedure could have benefit.

Reference

  1. Piazza G, Hohlfelder B, Jaff MR, Ouriel K, Engelhardt TC, Sterling KM, et al; SEATTLE II Investigators. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015 Aug 24;8(10): 1382-1392. doi: 10.1016/j.jcin.2015.04.020.