Myriad Novel Devices Aim to Boost Decongestion in Acute HF
Researchers are mulling how best to study these devices targeting cardiorenal syndrome as adjuncts to diuretics.
Getting patients with acute heart failure (HF) decongested continues to be a vexing problem, with many people failing to shed enough fluid over the course of days, weeks, or even months despite the use of oral and IV loop diuretics.
Not only is escalation of diuretics ineffective at addressing congestion in many cases, but also it can create additional issues, including neurohormonal activation and nephrotoxicity. That has researchers exploring new technological approaches to enhance decongestion, with the goals of making patients feel better and keeping them at home and out of the hospital.
Many of these strategies, mostly still in the early feasibility stage, were featured at the Technology and Heart Failure Therapeutics (THT) 2023 meeting in Boston, MA, last month. There were various “pullers” that reduce renal vein pressure and “pushers” that increase renal arterial pressure—both approaches entail temporary devices in the setting of cardiorenal syndrome—and a system (Aquapass) that leverages patients’ sweat glands to shed fluid. Attendees also heard about neuromodulation approaches involving cardiac pulmonary nerve stimulation and splanchnic nerve ablation, as well as systems for tailored diuretic dosing and self-administration of diuretics at home.
Congestion is the main driver of symptoms like bloating and shortness of breath in acute AF and the reason many patients decide to go the hospital.
“If they’re symptomatic, they’re functionally limited, and if they’re functionally limited, this is really what is impacting quality of life for them,” Navin Kapur, MD (Tufts Medical Center, Boston, MA), who gave a talk on pullers at the THT meeting, told TCTMD.
Moreover, persistent congestion has been associated with poor clinical outcomes, including higher rates of readmission and HF-related mortality, he noted.
Moving Beyond Diuretics
The continuing clinical need for additional solutions for congestion beyond diuretics along with pressure from public and private payers to reduce 30-day readmissions have combined to spur technological innovations in this area.
“To get to that decongested state with diuretics and drugs alone, that could take weeks, it could take months, and that’s really not sustainable for a healthcare system that is trying to keep people out of the hospital and also trying to reduce length of stay,” Kapur said. “This is why we’re trying to get a better handle on how to optimize diuretic selection, as well as escalation, and then this is where the technologies start to come into play.”
Loop diuretics have been the go-to option for decongesting patients with acute HF since they were first introduced in the 1960s. Newer agents that are now part of guideline-directed medical therapy (GDMT)—including the sodium-glucose cotransporter 2 (SGLT2) inhibitors and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (Entresto; AstraZeneca)— play a role as well.
But use of very high doses of diuretics alone or in combination with other agents raises concerns about tolerability, with effects on blood pressure, heart rate, and metabolic parameters, Kapur said. If you’re using five to seven drugs all at once, for instance, “you’re kind of stressing the system in some of those patients.”
Deciding to Add a Device
Addressing inadequate decongestion on diuretics, or so-called diuretic resistance, is complicated by the lack of a standardized definition of diuretic failure—at what point is it desirable to add something else to change the clinical course of the patient?
Jennifer Cowger, MD (Henry Ford Health, Detroit, MI), who gave talks on pushers such as the Aortix device, said adding a device would be worth considering in patients with severe congestion who develop severe biventricular filling pressure overload, a situation in which it will likely take a long time to see a decongesting effect from diuretics. Another plausible scenario for device use, she said, could be for patients who don’t have such severe pressure overload but still have congestion that is not responding to usual medical therapy, including IV diuretics at a reasonable dose and sequential nephron blockade.
Some have argued, Kapur noted, that physicians shouldn’t wait too long to determine that diuretics aren’t working and should start using a device to get the synergistic effects of drug and device to rapidly decongest patients after they are getting switched from oral to IV diuretics, for instance. That’s based on the idea that if you wait until someone is considered “diuretic refractory,” however that’s defined, you risk a very long length of stay and also off-target effects of drug therapy, which would make the situation more difficult for any device to address. “Because now you’ve exposed the kidney, for example, to highly nephrotoxic diuretics at high doses and you’re asking the device to really overcome, potentially, some of those effects,” Kapur said.
The Ideal Device
There are currently no US Food and Drug Administration-approved devices designed for the purpose of decongestion in acute HF, although renal replacement and ultrafiltration have been tried in the past to remove fluid, Kapur said.
There are multiple types of devices in the pipeline targeting different areas of fundamental cardiovascular physiology, he noted. For sicker patients who have low cardiac output and profound congestion—perhaps teetering on the edge of cardiogenic shock—one might want to use both a device that increases perfusion in the arterial system and one that reduces venous pressure in the kidney, he said. But for patients who are in better shape—who are congested but have normal blood pressure and no evidence of end-organ hypoperfusion, for instance—“that’s where I think some of these technologies may start to come into play.”
Multiple different device approaches are likely to find a role, Kapur said. “I think we’re going to see different buckets and different phenotypes with congestive heart failure that are best suited for specific technologies as we go forward.”
A requirement for all will be that they’re very safe since they’ll be used predominantly in an elderly population, Kapur stressed, noting that any invasive device carries the potential for vascular complications.
As for what the optimal device solution might be, “the jury’s out,” Cowger said. Theoretically, devices that provide direct blood flow to the kidneys may be beneficial because when the kidneys are congested, there’s neurohormonal activation and vasoconstriction of the arteries leading to the kidneys.
But regardless of the type of device, showing that it speeds decongestion and reduces length of stay will be critical, Cowger said. And she agreed with Kapur that safety is paramount, predicting, however, that vascular complications will decline over time as technologies mature and catheter sizes shrink.
Ultimately, a device that can be used by a patient at home for months or years to keep them out of the hospital would be ideal.
W. H. Wilson Tang, MD (Cleveland Clinic, OH), who discussed the concept of diuretic resistance at the THT meeting, indicated that there will be room for several different types of devices aimed at easing congestion. “I don’t think there’s a one-size-fits-all,” he told TCTMD. “I think it’s a mistake to think all acute decompensated heart failure presents the same way and needs the same thing.”
Clinical Trial Challenges
As companies move through early feasibility studies and start to think about pivotal trials designed to gain regulatory approval, some key questions need to be resolved. In addition to refining definitions of failed diuretic therapy or inadequate decongestion, trialists also will need to pin down which patients would be most likely to benefit and which endpoints will provide meaningful information on the safety and efficacy.
As Tang pointed out, there are many reasons that patients develop progressive congestion and require repeat visits to the hospital.
“It’s going to be very challenging for us as clinicians as well as for the FDA to interpret the meaning of those trials if we don’t have a consensus around what is the patient target population,” Kapur said.
Cowger said that as companies move into clinical trials for approval, safety and simplicity are going to be key because the largest population of potential device candidates will be those who aren’t too sick but have multiple recent admissions for congestion.
As for endpoints, she said data showing benefits beyond 30 days will be needed. “Just because we’re keeping somebody out of the hospital for 30 days doesn’t mean that it’s going to be a useful therapy. We need to see that it impacts outcomes,” Cowger said, pointing to measures like renal function, rehospitalization, and dyspnea scores at 6 months of follow-up or later.
There’s an active ongoing discussion among researchers, industry, and the FDA about these issues, Tang said, noting that no consensus has been reached. He questioned whether the FDA would approve a device based on an increase in urine output or whether the agency would require a reduction in rehospitalizations. Or could relief of symptoms, a patient-centric outcome, be enough?
“In situations where relieving congestion is inadequate despite diuretics, then the ability to overcome that is a reasonable endpoint,” Tang said. He suggested, though, that not knowing all of the effects of the various devices complicates the deliberations. “Until we actually figure out what these devices can do,” he said, “it’s difficult to tell what are the appropriate endpoints.”
More guidance needs to come from the FDA on the inclusion criteria for these trials, because companies don’t want to get into a situation where they initiate a trial and then find out the endpoints aren’t deemed good enough, Tang said. He didn’t single out a particular endpoint that would be considered clinically meaningful, but said “the patient-centric endpoints are as important as the hard endpoints.”
Field in the ‘Call-to-Action Phase’
All of the new technologies in the pipeline addressing diuretic resistance make this a fun time to be working in heart failure research, Cowger said. Over the coming years, device companies will learn from each other and the FDA about how trials should be designed and conducted and consensus will develop around how to define diuretic resistance and decongestion, she predicted, adding that these harmonized definitions will be critical when comparing how different devices perform across studies.
In addition, Cowger sees devices getting smaller and smaller over time, and technologies that allow for device-based decongestion at home emerging.
“When will that be? A decade from now probably. Will it be in 3 years? Very unlikely. But I think it’s in the near future,” she said.
Initial studies will focus on the sickest patients with the fewest options, and if devices clear those hurdles, they’ll start moving into less-sick cohorts, where there may be even greater opportunities to observe a benefit in terms of keeping patients alive and out of the hospital, Cowger said.
“That’s kind of what we’re looking at with heart failure, right? It’s really hard now to impact mortality. A lot of it is: can we keep our patients alive and out of the hospital with a good quality of life longer? And I think this is where these devices are going to have a particular niche—shortening lengths of stay, and then once they’re fully implantable, keeping them at home,” she said.
For Kapur, the field of device solutions for inadequate decongestion in acute HF is in the “call-to-action phase,” in which clinicians, industry, and regulators are working out the particulars for future clinical research. And this work is important, he stressed. “We should continue innovating because our patients desperately need it.”
In recent years, new ideas and new therapies have not been holding back this field so much as sluggish implementation and inequitable access. Amid all the excitement over innovation, Tang made the case for making sure that there is as much enthusiasm for accessibility and implementation.
As the technologies themselves evolve, clinicians still need a better understanding of the fundamental pathobiology of why some patients respond to diuretics and others don’t, Tang argued. “The science of understanding the cardiorenal interaction should also be an equally important focus.”
- Tang reports receiving consulting fees/honoraria/speaking fees from Sequana Medical AV, Owkin, Applied Therapeutics Inc, Relypsa Inc, preCARDIA, Genomics plc, Cardiol Therapeutics Inc, the American Board of Internal Medicine, Springer Nature, Boston Scientific, WhiteSwell, Renovacor Inc, Zehna Therapeutics LLC, and CardiaTec Biosciences, as well as grant support/research contracts from Alnylam Pharmaceuticals, Pfizer/Array Biopharma, 3Live Inc, SalubrisBio, Bristol Myers Squibb, Pfizer, BioCardia Inc, and Cordio.
- Cowger reports receiving consulting fees/honoraria/speaking fees from Biotronik, Medtronic, Abbott Vascular, and Zoll, as well as having equity/stock(s)/options from Procyrion.
- Kapur reports receiving grant support/research contracts from Abiomed and Boston Scientific and consulting fees/honoraria/speaking fees from Abbott Vascular, Abiomed, Boston Scientific, LivaNova, and preCARDIA.