It's still early days for a potential transcatheter technique that tones down sympathetic activation mediating blood volume shifts to the heart and lungs. Such volume transfers can contribute to congestion and acute decompensation in some patients with heart failure. But a randomized trial with negative overall results still may have moved the novel procedure a modest step forward.
The procedure, right-sided splanchnic-nerve ablation for volume management (SAVM), failed to show significant effects on hemodynamics, exercise capacity, natriuretic peptides, or quality of life in a trial covering a broad population of patients with heart failure with preserved ejection fraction (HFpEF).
The study, called REBALANCE-HF, compared ablation of the right greater splanchnic nerve (GSN) to a sham version of the procedure for any effects on hemodynamic or functional outcomes.
But a secondary analysis identified a subgroup of patients, more than half the total, with a profile of features characterizing them, researchers say, as a group likely to respond favorably to SAVM.
Among such "potential responders," those undergoing SAVR trended better than patients receiving the sham procedure with respect to hemodynamic, functional, natriuretic peptide, and quality-of-life endpoints.
The potential predictors of SAVM success included elevated or preserved cardiac output and pulse pressure with exercise or on standing up; appropriate heart-rate exercise responses; and little or no echocardiographic evidence of diastolic dysfunction.
The panel of features might potentially identify patients more likely to respond to the procedure and perhaps sharpen entry criteria in future clinical trials, Marat Fudim, MD, MHS, Duke University Medical Center, Durham, North Carolina, told theheart.org | Medscape Cardiology.
Fudim presented the REBALANCE-HF findings October 8 at the Heart Failure Society of America (HFSA) 2023 Annual Scientific Meeting in Cleveland, Ohio.
How SAVM Works
Sympathetic activation can lead to acute or chronic constriction of vessels in the splanchnic bed within the upper and lower abdomen, one of the body's largest blood reservoirs, Fudim explained. Resulting volume shifts to the general circulation, and therefore the heart and lungs, are a normal exercise response that, in HF, can fall out of balance and excessively raise cardiac filling pressure.
Lessened sympathetic tone after unilateral GNS ablation can promote splanchnic venous dilation that reduces intrathoracic blood volume, potentially averting congestion, and decompensation, observed Kavita Sharma, MD, invited discussant for the Fudim presentation.
The trial's potential-responder cohort "seemed able to augment cardiac output in response to stress" and to "maintain or augment their orthostatic pulse pressure," more effectively than the other participants, observed Sharma, of Johns Hopkins University School of Medicine, Baltimore, Maryland.
Although the trial was overall negative for 1-month change in pulmonary capillary wedge pressure (PCWP), the primary efficacy endpoint, Sharma said, it confirmed SAVR as a safe procedure in HFpEF and "ensured its replicability and technical success."
Future studies should explore ways to characterize unlikely SAVM responders, she proposed. "I would argue these patients are probably more important than even the responders."
Yet it's unknown why, for example, cardiac output wouldn't increase with exercise in a patient with HFpEF. "Is it related to preload insufficiency, right ventricular failure, atrial myopathy, perhaps more restrictive physiology, chronotropic incompetence, or medications ― or a combination of the above?"
REBALANCE-HF assigned 90 patients with HFpEF to either the active or sham SAVM groups, 44 and 46 patients, respectively. To be eligible, patients were stable on HF meds and had either elevated natriuretic peptides or, within the past year, at least one HF hospitalization or escalation of intravenous diuretics for worsening HF.
The active and sham control groups fared similarly for the primary PCWP endpoint and for the secondary endpoints of Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score, 6-minute walk distance (6MWD), and natriuretic peptide levels at 6 and 12 months.
Predicting SAVM Response
In analysis limited to potential responders, PCWP, KCCQ, 6MWD, and natriuretic peptide outcomes for patients were combined into Z scores, a single metric that reflects multiple outcomes, Fudim explained.
The Z scores were derived for tertiles of patients in subgroups defined by a range of parameters that included demographics, medical history, and hemodynamic and echocardiographic variables.
Four such variables were found to interact across tertiles in a way that suggested their value as SAVM outcome predictors and were then used to select the cohort of potential responders. The variables were exertion-related changes in cardiac index, pulse pressure, and heart rate, and mitral E/A ratio ― the latter a measure of diastolic dysfunction.
Among potential responders, those who underwent SAVR showed a 2.9 mm Hg steeper drop in peak PCWP at 1 month (P = .02) compared to patients getting the sham procedure.
They also bested control patients at both 6 and 12 months for KCCQ score, 6MWD, and natriuretic peptide levels, the latter of which fell in the SAVR group and climbed in control patients at both follow-ups.
"Hypothetically, it makes sense" to target the splanchnic nerve in HFpEF, and indeed in HF with reduced ejection fraction, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, Texas, told theheart.org | Medscape Cardiology.
And should SAVM enter the mainstream, it would definitely be important to identify "the right" patients for such an invasive procedure, those likely to show "efficacy with a good safety margin," said Bozkurt, who was not associated with REBALANCE-HF.
But the trial, she said, "unfortunately did not give real signals of outcome benefit."
REBALANCE-HF was supported by Axon Therapies. Fudim discloses consulting, receiving royalties, or having ownership or equity in Axon Therapies. Sharma discloses receiving honoraria for speaking from Novartis and Janssen and serving on an advisory board or consulting for Novartis, Janssen, and Bayer. Bozkurt discloses receiving honoraria from AstraZeneca, Baxter Health Care, and Sanofi Aventis and having other relationships with Renovacor, Respicardia, Abbott Vascular, Liva Nova, Vifor, and Cardurion.
Heart Failure Society of America (HFSA) 2023 Annual Scientific Meeting: Presented October 8, 2023.
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Cite this: Hopeful Insights, No Overall HFpEF Gains From Splanchnic Nerve Ablation: REBALANCE-HF - Medscape - Oct 12, 2023.