Meet the Trialist: The “Sweet Spot” from RELIEVE-HF

Medicom spoke with Prof.Gregg Stone (Icahn School of Medicine at Mount Sinai, NY, USA) about the results of the RELIEVE-HF trial (NCT03499236), which he shared during the ACC 2024 Scientific Session, held in Atlanta, USA [1].

The RELIEVE-HF trial evaluated the efficacy of interatrial shunting using the Ventura shunt in heart failure (HF) patients with reduced (HFrEF) and preserved ejection fraction (HFpEF). This global study randomised 508 participants to receive either the shunt or a placebo procedure, alongside optimal medical therapy. The study's primary endpoint—combining mortality, heart transplant or device implantation, HF hospitalisations, outpatient worsening, and quality of life changes—showed no significant difference between the shunt and placebo groups.

Notably, a prespecified subgroup analysis revealed that participants with HFrEF benefitted from the shunt, particularly in reduced HF hospitalisations, whereas HFpEF patients experienced increased death rates and hospitalisations, suggesting the intervention's benefits and risks are contingent on the type of heart failure. These findings highlight the importance of patient selection based on ejection fraction status in clinical decisions regarding interatrial shunting.

RELIEVE-HF highlighted notable differences in outcomes between HFrEF and HFpEF. What does this imply about the underlying pathophysiological distinctions?

"The primary takeaway from RELIEVE-HF is that the Ventura interatrial shunt is very safe for a severely ill HF population, though it didn't demonstrate overall efficacy. However, we observed a significant contrast in treatment effects between patients with reduced and preserved EF. Those with a baseline EF ≤40% saw substantial benefits, including a near 50% reduction in CV events and notably in HF hospitalisations. Conversely, for those with an EF ≥40%, the outcomes were detrimental, showing increased hospitalisations and a tripling in mortality. This suggests a potential role for interatrial shunts in patients with reduced EF, while their use in patients with preserved EF should be extremely cautious, if considered at all.

We have baseline and 1-year transthoracic echocardiographic data. Both HFrEF and HFpEF patients show increased left atrial volume and similar median pressures around 16 mmHg. However, their cardiac structures differ significantly; HFrEF patients have a dilated and weak left ventricle, accommodating the increased flow from the shunt. In HFpEF, the ventricles are normal-sized but stiff, leading to complications when accommodating additional fluid. This results in increased tricuspid regurgitation, pulmonary artery pressure, and potentially detrimental shifts in cardiac output."

Given these findings, would you recommend modifications to selection criteria for future studies or the clinical use of interatrial shunts in HF?

"Considering the baseline event rates in our study, there remains a substantial clinical need in HFrEF patients who had a significantly higher annual event rate compared with HFpEF patients. Future studies like ALLAY-HF (NCT05685303) and RESPONDER-HF (NCT05425459) are targeting a different, lower-risk HFpEF population. From what we've learned, HFrEF patients benefit markedly from shunt interventions, suggesting this group should remain a primary focus in future trials.

In the original REDUCE LAP-HF II trial (NCT03088033), it was surprising to see almost no mortality among the participants, given that they were an HF population [2]. The participants were considered low risk; eligibility required only exercise-induced increased pulmonary capillary wedge pressure. Although the overall results of the trial were negative, there appeared to be a subgroup within this very low-risk cohort that was at an even lower risk, showing lower natriuretic peptide levels and better cardiac function without right heart involvement. I believe there is a sweet spot for a small subset of patients with HFpEF, where shunts may not reduce their already low mortality risk, and these patients are also unlikely to require hospitalisation for HF. However, the real sweet spot identified in this trial was among patients with HFrEF. Despite only 206 participants randomised for shunt placement, a significant benefit was observed, marked by a P-value of less than 0.0001."

Do you support further testing of interatrial shunts in HFpEF patients?

"The findings from RELIEVE-HF open significant possibilities for HFrEF patients who have a great clinical need. We anticipate more clinical trials exploring various interatrial shunt designs tailored to this group. While HFpEF patients showed adverse effects, this insight is crucial for refining future interventions and could potentially redefine treatment approaches in HF management. I expect to see a lot more clinical trial activity, and we're going to learn a lot more in the next 5 years."

1. 
   
   1. Stone GW. A double-blind, randomized, placebo-procedure-controlled trial of an interatrial shunt in patients with HFrEF and HFpEF: principal results from the RELIEVE-HF trial. ACC 2024 Scientific Session, 6–8 April, Atlanta, USA.
   2. Shah SJ, Lancet. 2022;399(10330):1130-1140.

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Posted on 15 May 202413 June 2024