The PE Pipeline: Evidence Trickles in for Catheter-Based Therapies

MIAMI BEACH, FL—The jury’s still out on which treatment is best for patients with intermediate-risk pulmonary embolism (PE), particularly whether catheter-directed thrombolysis (CDT) and mechanical thrombectomy have an impact on hard outcomes above and beyond anticoagulation alone. Upcoming trial results may provide some relief to clinicians making hard decisions in the absence of evidence, according to a spate of presentations at ISET 2023.

“There’s a long pipeline of device trials” in the works, said Akhilesh Sista, MD (Weill Cornell Medicine, New York, NY). “This has its pluses and minuses. We as a community need to make sure that, yes, new devices and new innovative therapies are available, but we also need to not put the cart before the horse, because the [current] data is inadequate.”

Just Two Randomized Studies

Studies of thrombolysis have included SEATTLE II (n = 150), RESCUE (n = 109), OPTALYSE PE (n = 101), PERFECT (n = 100), CANARY (n = 94), SUNSET sPE (n = 81) and ULTIMA (n = 59). Among them, only CANARY and ULTIMA involved a randomized comparison between lysis plus anticoagulation and anticoagulation alone.

Sista, referring to the 2013 ULTIMA trial, published in 2013, observed: “I used to say that this was the only piece of evidence that catheter-directed lysis actually works and this is the only thing we can point to: which is that it reduces the RV/LV ratio at 24 hours by echocardiography compared to anticoagulants alone.” CANARY followed in 2022, but data still are absent for hard outcomes.

There are some risks with CDT—Sista cited a 2017 meta-analysis showing a 4.65% rate of major bleeding/vascular injury and a 0.35% risk of intracranial hemorrhage. “We think we’re getting better at this with new technology and new algorithms for the administration for fibrinolytic drugs,” he added, such that in RESCUE the rate with the Bashir endovascular catheter (Thrombolex) was below 1% within 72 hours. “That being said, there are now technologies that are removing thrombus without using fibrinolytic drugs,” examined by studies such as FLARE, EXTRACT-PE, and FLASH.

But without control groups—which were used only in ULTIMA and CANARY—it’s impossible to definitively know how these devices perform in comparison to best medical therapy, Sista specified.

We as a community need to make sure that, yes, new devices and new innovative therapies are available, but we also need to not put the cart before the horse. Akhilesh Sista

Current guidelines are supportive of the quest for more data, though as yet they don’t give strong recommendations. Use of surrogate outcomes is one aspect holding the field back, as is the small number of patients studied—for comparison, Sista pointed out that more than 1,500 participants have been randomized in clinical trials of systemic lytics. Additionally, longer follow-up is needed due to studies showing that some patients continue to have reduced peak oxygen consumption 6 months to 1 year after PE.

Two new studies are trying to meet this need by comparing catheter-based interventions against anticoagulation: HI-PEITHO and PE-TRACT, for which Sista is national principal investigator.

With results from PE-TRACT, which involves a mix of both CDT and mechanical thrombectomy in the intervention arm, hopefully clinicians will “be able to confidently advise an anxious intermediate-risk patient, to individualize care knowing whether [intervening] actually reduces RV/LV ratio at 48 hours and whether PA obstruction actually goes down because of what we do and whether that matters as we correlate that with actual clinical outcomes,” he said. The trial also aims to provide clarity on patients with persistent dyspnea after treatment and may reveal potential biomarkers or insight into clot biology, greater benefit for either CDT or mechanical thrombectomy, factors to guide risk stratification, and other information.

Ultimately, the trial may provide guideline-writing committees with the evidence they need to make level 1 recommendations, said Sista. He acknowledged, however, its findings won’t be available for another 6 years.

Sista noted that there are three main options for CDT: standard infusion catheter, the ultrasound-assisted EKOS system (Boston Scientific), and the Bashir endovascular catheter.

Devices without a fibrinolytic drug “on the horizon,” said Sista, are the AlphaVac mechanical aspiration device (AngioDynamics) and the JETi (Abbott) thrombectomy device, both set to be looked at in single-arm studies, and many companies are working to develop such technologies. PEERLESS, currently enrolling patients, will compare the Flowtriever (Inari Medical) versus CDT without an anticoagulation-only arm.

“It’s very exciting, but there are some consequences to having this many studies going on at the same time,” Sista observed. For instance, enrollment could prove challenging.

Unknown Risk-Benefit Ratio

Ramsey Al-Hakim, MD (Scripps Health, La Jolla, CA), said that right now it’s hard to weigh risk versus benefit when it comes to the various options. While catheter-directed treatments are known to reduce RV/LV ratio in the short term, nearly half of patients continue to have exercise limitations 1 year later and about 3% have chronic thromboembolic pulmonary hypertension, he told the ISET audience. The questions, then, are: “What is the mortality benefit? And what is the long-term benefit, if there is any? . . . With these interventions, which are costly and do have risks associated with them, are we ultimately helping our patients?”

Treatment choices are all the more complex because of the wide range of available options, said Keith M. Sterling, MD (Inova Alexandria Hospital, VA), who also spoke in the ISET session. CDT, he added, is “very readily available, it’s very easy to use, you can do it reproducibly, it’s pretty quick time to treatment, and we also at least have some data to show efficacy and safety.”

While the evidence arrives, Sterling recommended that clinicians seek inspiration from the PERT Consortium when making decisions in this space.

With these interventions, which are costly and do have risks associated with them, are we ultimately helping our patients? Ramsey Al-Hakim

In “the small but real population” with high-risk PE, the advice is to consider catheter or surgical embolectomy for patients with an absolute contraindication to thrombolysis, while full-dose systemic thrombolysis is considered for those with no contraindication. Only for patients with a “relative” contraindication is CDT (or reduced-dose systemic thrombolysis) an option. But in the larger population of patients with submassive, intermediate-risk PE, “basically you either have an absolute contraindication to lysis or not, [in which case] you should consider catheter-directed thrombolysis,” he explained.

Al-Hakim noted that even within the intermediate group there are nuances.

With intermediate-low risk, the systemic approach is “probably adequate,” he said. For intermediate-high risk, that anticoagulation should be paired with “close monitoring,” said Al-Hakim. “Now, what does close monitoring mean? This is where I really want to get into the fine print to try to help everyone understand when you’re called and you’re asked to do an intervention, what are the things we really should be looking at?”

It’s important for the care team to pay attention to signs of clinical deterioration—such as decreasing systolic BP, increasing heart rate, worsening gas exchange, inadequate perfusion, worsening RV function, rise in cardiac biomarkers—rather than wait until patients progress to the high-risk category, Al-Hakim advised. “Not hypotension, but just signs that they’re not headed the right way with anticoagulation alone.”

Lysis vs Thrombectomy

Sterling, whose talk largely supported CDT, pointed out that the treatment is not without issues. With thrombectomy it’s thought that “you get more thrombus, you can get it out quicker in a sicker patient population, you [may not] need an ICU,” he said. But “you can’t, with an aspiration device, get out into the periphery. . . . You get that with lysis.”

Additionally, results from the PERT Consortium database suggest that mortality is lower with catheter-directed thrombolysis than with thrombectomy in high-risk patients without increasing bleeding, he pointed out. And in intermediate-risk patients, mortality was similar between the two treatments but bleeding was less common with thrombolysis.

Whether these patterns will bear out in further research isn’t certain, Sterling noted.

“Thrombolysis works,” agreed Ripal T. Gandhi, MD (Miami Cardiac & Vascular Institute, FL), whose presentation focused on the assets of mechanical therapy shown in the FLASH registry. Still, he too mentioned bleeding concerns with lytics and said a growing evidence base could help cement practice patterns: “Mechanical thrombectomy can rapidly extract thrombus and relieve RV strain without thrombolytics; additional data on the risk-to-benefit ratio could shift the standard of care,” he commented.