More Early Insights Into Interatrial Shunts in HF, but Little to Focus the Field

BOSTON, MA—This week’s Technology and Heart Failure Therapeutics (THT) 2023 meeting featured more than a dozen talks on interatrial shunts to reduce left atrial pressures and volume overload in heart failure. But there remains a lack of definitive clues as to how this field might be focused, and the horizon remains hazy.

Looking at a range of surprisingly diverse technologies, all of the presentations at this year’s meeting were first-in-human snapshots, small pilot studies, observations from roll-in cohorts, or post-hoc analyses from the only randomized trial to date. Some devices are permanent shunts, others are cutting tools that puncture a hole in the septum. Some trials are focused on heart failure with preserved ejection fraction (HFpEF), others are enrolling across the spectrum of heart failure. Some investigators are using invasive hemodynamic tests to select patients, others are relying on clinical symptoms. Some shunts are as small as 5 mm, others are as large as 10 mm.

Experts discussing this year’s talks with TCTMD agreed: whether one approach will win out over the rest is no clearer after THT 2023 than it was going in, but this speaks to the enthusiasm the left-atrial-unloading hypothesis has inspired.

“I think the reason there's all this activity is because the shunt is an easy device to implant and if it provides a clinical benefit, it would be widely used,” Daniel Burkhoff, MD, PhD (Cardiovascular Research Foundation, New York, NY), told TCTMD.

Each approach will have to stand on its own merits, although obviously a positive study from one would help boost the entire field. Daniel Burkhoff

To date, REDUCE LAP-HF II, testing Corvia Medical’s interatrial shunt device (IASD) in HFpEF, is the only randomized, sham-controlled study that has been completed, and it found no benefit to shunt placement. But as TCTMD reported when the results were unveiled at last year’s THT meeting, investigators did identify responder and nonresponder groups. Patients who did not have evidence of latent pulmonary vascular disease (PVD) on invasive exercise tests appeared to benefit from shunt placement, whereas those with latent PVD fared worse, as did patients with pacemakers.

Speaking with TCTMD here, lead investigator for that randomized trial, Sanjiv Shah, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), said there’s just not the statistical power to make much of the signals seen in the small, open-label studies presented at this year’s conference. “All kinds of things can happen when people know they’re getting a device,” Shah noted.

But despite the letdown of REDUCE LAP-HF II, he continued, “there's still a lot of optimism in the field. There's still a huge unmet need, and I think that the fact that we saw a benefit of some kind in the Corvia trial, in half the patients, is really helpful. If we didn't find any subgroup that improved, I think that would've been really a damper on the field.”

Who Will Benefit?

REDUCE LAP-HF II investigators are urging the incorporation of invasive hemodynamics into new or ongoing trials, but so far it’s not clear whether other trials will identify the same subgroup or, indeed, whether they’ll even be able to look. The second sham-controlled trial expected to report results within the year is RELIEVE-HF, testing the V-Wave shunt (Ventura). That study has now completed enrollment of approximately 600 patients across the spectrum of HF and, notably, is not performing invasive exercise tests.

Meanwhile, the PRELIEVE pilot study, presented at THT 2023, included a mixed population of HFrEF and HFpEF patients treated with either an 8-mm or 10-mm atrial flow regulator (Occlutech). In data presented by Gregg Stone, MD (Icahn School of Medicine at Mount Sinai, New York, NY), on behalf of Martin W. Bergmann, MD (AK Altona, Hamburg, Germany), efforts to identify “super-responders” by zeroing in on the fewer than 50% of patients who improved both on the 6-minute walk test and had a 5-point or greater improvement in quality of life according to the Kansas City Cardiomyopathy Questionnaire found no clinical or hemodynamic parameters, including any baseline right-sided measures or pulmonary pressures, that could help predict whether they’d improve with a shunt.

The pivotal FROST-HF trial has now kicked off with the aim of randomizing approximately 700 patients 1:1:1 to a sham procedure or to an 8-mm or 6-mm Occlutech shunt—the smaller size potentially reflecting the evolving hypothesis that smaller shunt sizes may preferable—but it is enrolling patients based on “resting clinical parameters, not exercise parameters,” Stone said.

I've been surprised at how much funding has gone towards this, especially after our neutral trial. Sanjiv Shah

Asked whether he thinks invasive hemodynamics at rest and exercise to uncover latent PVR will prove important, Burkhoff said there are, as yet, no new data to inform this opinion. “The only way that you can sort that out is by [awaiting] the results of the definitive clinical trials,” Burkhoff told TCTMD. In REDUCE LAP-HF II, he said, they had the invasive testing information, so that formed the basis for identifying a responder group. “They also obviously have all the noninvasive information to go by, but that noninvasive information did not lead to a positive subgroup,” he noted.

Indeed, a presentation at THT 2023 looking at obese patients in REDUCE LAP-HF II—a group more likely to have “responder characteristics” (fewer pacemakers, lower exercise PVR, less atrial fibrillation)—indicated that this subgroup is no more or less likely to respond well to an atrial shunt.

Burkhoff predicted ongoing trials that are not doing invasive hemodynamics may identify other subgroups that do or do not respond—that’s the nature of clinical research. “I don't know that one single study will be definitive either way, because the different studies have subtle differences and inclusion criteria, [and there] are differences in the devices and differences in what they’re measuring,” he said. “Each approach will have to stand on its own merits, although obviously a positive study from one would help boost the entire field.”

Move the Hole?

The Apture transcatheter shunt system (Edwards Lifesciences) is taking yet another approach: the ALT-FLOW early feasibility study was presented during a THT late-breaking clinical trial session and published simultaneously in JACC: Cardiovascular Interventions. This device differs from the other implantable shunts in that rather than passing through the septum, it creates an atriotomy between the left atrium and the coronary sinus. The aperture is then maintained with a nitinol-based stent, allowing hemodynamics to “follow the natural flow path” while minimizing the risk of right-to-left paradoxical embolism, as presenter William Gray, MD (Lankenau Heart Institute, Wynnewood, PA), explained to TCTMD.

Among the 78 out of 87 patients successfully treated with this device, functional class and quality of life improved and pulmonary capillary wedge pressures went down, without changes in right heart function, similar to the kinds of changes seen with the other early contenders.

In an exploratory analysis prompted by REDUCE LAP-HF II, Gray said, ALT-FLOW investigators divided their patients according to whether they had evidence of latent pulmonary vascular resistance or not and found no difference in shunt efficacy. “So, we looked for that signal, and didn't find it,” he said.

Nevertheless, he said, “I'm buoyed by these results, but with appropriate caution because of the nonrandomized nature of the trial. Having said that, I do think that there's a lot of work to do to prove this is going be a successful strategy. From a trial standpoint, we really have to define the right patients and measure the right outcomes, but I think we're getting there.”

No-Implant Shunts

Finally, THT attendees got a glimpse at early results with two no-implant devices, the Alleviant system and the PAS-C atrial shunt (InterShunt), which create openings of 7 mm and 6 mm, respectively, but leave no supporting materials against the septum that might complicate later cardiac interventions (a third no-implant device not featured at the meeting, the Noya, has an adjustable 8-mm aperture). The advantage of leaving nothing behind, argued Saibal Kar, MD (Los Robles Health System, Los Angeles, CA), who presented 6-month results from the EASE HF open-label study of the PAS-C device, might be that the septal opening might be more compliant to the hemodynamic changes during the cardiac cycle.

Burkhoff called that theory “intriguing” but said here, too, investigators need to have imaging results to back up these claims, and beyond that would need to demonstrate that a more-dynamic aperture would lead to better outcomes.

I think there's good reason to be skeptical, but there's also good reason to try to figure it out. William Gray

For the time being, there’s little to take away from the flurry of early studies, except that the field remains active.

“I've been surprised at how much funding has gone towards this, especially after our neutral trial,” Shah said. “Clearly people believe in it, and enough to spend a lot of money on it.” If nothing more, he added, investigators are getting a chance to really learn a lot about how to do interventional heart failure trials and the kinds of imaging, tools, and techniques required.  

Burkhoff stressed that the main takeaway from all of these early studies is that the hemodynamic hypothesis has borne out.

“What we've learned [as of] today, which has been clear, is that the results of all of the preliminary studies show that shunting reduces wedge pressure at rest and exercise, and more so at exercise. No matter what the configuration, whether it's an implant or no implant, whether it's 5 mm or 8 mm, we're seeing very similar reductions in wedge pressure in the range of 3 to 5 to 6 mm Hg reduction—I think one study even showed 7,” he said. “The question is whether or not the hemodynamic responses that we see translate into clinical benefits—that's really the big question.”

Gray’s prediction is that interatrial shunting won’t be a “solitary solution” in heart failure.

“I think it'll be much like renal denervation in the sense that if it does show efficacy at some point, it's going to be one of several therapeutics that these types of patients will likely have to have in their lives.” Shunt therapy, in the right patients, would be used on top of optimal medical therapy or potentially as a means to reduce the total medication burden, he said. “That's the hope, but that's only if it works. We don't know that yet because there’s never been a positive trial. So, I think there's good reason to be skeptical, but there's also good reason to try to figure it out.”