Interventional Options and Future Directions for Acute PE: New AHA Statement
The document gives an update on existing treatments and suggestions for how to obtain quality evidence.
Amid rapid changes in the field of acute pulmonary embolism (PE) treatment, the American Heart Association (AHA) has released a scientific statement summing up the current state of interventional therapies and offering recommendations for future studies that can deliver the high-quality evidence currently lacking.
More than 5 years ago, the vast majority of patients hospitalized for acute PE—the third leading cause of CV death behind MI and stroke—were treated with anticoagulation alone, but now there are a variety of thrombus-removal strategies available, Jay Giri, MD (University of Pennsylvania, Philadelphia), chair of the writing group, explained to TCTMD. These include systemic thrombolysis, surgical embolectomy, and catheter-based therapies.
The last category is the focus of the new statement, which was published online October 4, 2019, ahead of print in Circulation to coincide with its presentation at the Pulmonary Embolism Symposium in Boston, MA.
There’s been renewed interest in this area, perhaps related to a desire to find out whether the outcomes of acute PE can be improved through a similar process that occurred with both MI and stroke, in which treatments progressed from medical therapies to endovascular interventions, Giri said.
"Part of this might be folks looking at PE as a disease process that might be ripe for the same evolution, with it being a disease that is associated with mortality and significant morbidity and cost and quality-of-life decrements,” he said, noting, however, that what worked for one disease will not necessarily work for another.
Even so, there are already commercially available devices designed for treating acute PE, with many more in the pipeline. “We do not think that the community has a good handle on where we're at with these devices, what the devices actually are, what the rationale for their use and the risks and benefits are,” Giri said. “And then secondarily, we also didn't think that there has been any kind of effort to lay out what the scientific agenda for evaluating these devices should be. That scientific agenda was very clear in the history of the development of endovascular therapies for myocardial infarction and stroke. It is anything but clear in the development of evidence for PE.”
We do not think that the community has a good handle on where we're at with these devices, what the devices actually are, what the rationale for their use and the risks and benefits are. Jay Giri
The new scientific statement, written by 12 experts split evenly between invasive and noninvasive physicians, starts by introducing various risk stratification tools for PE—all of which have important limitations, the authors say.
There are then several sections defining and reviewing various interventional therapies classed into two main categories: catheter-directed thrombolysis and catheter-based embolectomy. The authors note that there are currently two systems approved by the US Food and Drug Administration for use in acute PE—the EkoSonic endovascular system (Boston Scientific) and the FlowTriever embolectomy device (Inari Medical). Risks and expected benefits of those and other devices, rationale for their use, and patient selection are all covered.
Overall, existing evidence for these devices is poor, “and that's why that brings us to the next part of the document where we wanted to try to lay out the scientific research agenda for the devices,” Giri said. That discussion, which takes into consideration the current US regulatory environment, is broken into two parts—one for high-risk PE and one for intermediate-risk PE.
Even though randomized trials would be ideal in both settings, they might not be feasible for high-risk patients, many of whom are not good candidates for systemic thrombolysis, a likely comparator in any trial, the authors note. Other obstacles to randomization in this setting include likely crossovers due to the use of multiple interventions together and the need for mechanical circulatory support in some patients. In addition, it might be difficult to enroll enough patients because of the low incidence of high-risk PE, they say. “Hence, nonrandomized evaluations with prespecified performance goals for clinical effectiveness are reasonable in high-risk PE,” the authors say.
“Our argument here was that we thought it's likely unfeasible to randomize patients with high-risk PE to device therapy versus no device therapy,” he explained. “But that doesn't mean that the devices shouldn’t be studied rigorously in single-arm studies prospectively to set benchmarks to sort out their efficacy profile, for mortality ideally. And then from a safety standpoint, obviously that could theoretically be managed in large registries as well.”
That might be controversial to some, Giri acknowledged, but “to be honest with you, I do not think it would be very controversial among clinicians who actually encounter and treat these patients in the trenches in hospitals.”
The section on research in intermediate-risk PE is more detailed, Giri said, noting that in this population, the balance between the short-term mortality risk in anticoagulation-treated patients and rates of complications with interventional devices is more even than it would be in high-risk PE. When that’s the case, “randomization is necessary to truly get the data that is needed to use these devices in intermediate-risk patients,” Giri said, adding that the document provides a table of recommended endpoints—favoring hard clinical endpoints and patient-centric outcomes over surrogates—for future studies.
Influencing the type of data that will be available as new devices move through the pipeline and enter the market is how the FDA classifies interventional devices for treating acute PE. Giri pointed out that the two FDA-cleared devices for acute PE are designated as Class II, meaning they carry a moderate risk to patients. Class III, or high-risk, devices include other interventional therapies like transcatheter heart valves, left atrial appendage occlusion devices, and drug-coated balloons.
This distinction is important because Class III devices have to go through the more rigorous premarket approval (PMA) process by the FDA, Giri said. The bar is lower for Class II devices, which go down the 510(k) pathway.
“The question is first: is that classification appropriate?” Giri said. “And while it's not our job as an AHA scientific committee to tell the FDA how to classify, I think the implication is clear that we're skeptical of . . . where that threshold is being drawn, and it seems inconsistent when compared to other endovascular therapies that we use certainly as interventional cardiologists or interventional radiologists.”
Why this matters is that “you can expect there to be a lot of devices on the market without a lot of evidence to guide physicians in making decisions and not a lot of information for physicians to counsel patients with that is rigorous,” Giri said. He added that there’s no incentive for industry to sponsor studies that are more rigorous than those required for FDA approval, so funding will have to come from other sources.
The spread of multidisciplinary PE response teams (PERTs)—the subject of the final section in the consensus document—might help provide some of that additional evidence of safety and effectiveness, Giri said. “Where there is some promise is for PERTs to serve as a backbone of evidence development in a couple of different ways,” he said, singling out the PERT Consortium registry as a potential source of information on safety signals and possibly as a clinical trials network for PE.
Ultimately, Giri said, he hopes this new consensus statement will have an impact in a couple of ways.
“It’s primarily an educational tool where I want docs on both sides, interventionalists and noninvasive specialists, to be able to just get more objective information on how to think about when to use these therapies in their own mind and, most importantly, how to have these discussions with patients in this area where there are so many gray areas, particularly in an intermediate-risk PE population,” Giri said.
A second major goal is to influence how future studies are conducted, with the aim to obtain more high-quality evidence like that seen with other interventions, such as TAVR, he said.
“There was a clear agenda for how to develop that data in the most rigorous way over a decade, and everybody's winning as the field continues to develop that way,” Giri said.
Photo Credit: Jay Giri
Giri J, Sista AK, Weinberg I, et al. Interventional therapies for acute pulmonary embolism: current status and principles for the development of novel evidence—a scientific statement from the American Heart Association. Circulation. 2019;Epub ahead of print.
- Giri reports no relevant conflicts of interest.